Quinuclidine derivatives and medicinal compositions containing the same

ABSTRACT

The invention provides 1-phenethyl-3 (R)-(9[H]-xanthene-9-carbonyloxy)-1 -azoniabicyclo[2.2.2]octane in salt form, pharmaceutical compositions comprising it, and methods of using it for treatment of respiratory disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.11/325,059, filed Jan. 3, 2006, now U.S. Pat. 7,196,098 which is adivisional of U.S. patent application Ser. No. 11/116,777, filed Apr.28, 2005 (now U.S. Pat. No. 7,078,412), which is a continuation of U.S.patent application Ser. No. 10/740,264, filed Dec. 17, 2003 (now U.S.Pat. No. 7,109,210), which is a divisional of U.S. patent applicationSer. No. 10/047,464, filed Jan. 14, 2002 (now U.S. Pat. No. 6,750,226),which is a continuation of International Application No. PCT/EP00/06469,filed Jul. 7, 2000, and published in English on Jan. 18, 2001, whichclaims the benefit of Spanish Application No. P9901580, filed Jul. 14,1999, the contents of each of which are incorporated herein byreference.

The novel structures according to the invention are antimuscarinicagents with a potent and long lasting effect. In particular, thesecompounds show high affinity for muscarinic M₃ receptors(Hm3).

In accordance with their nature as M₃ antagonists, the new compounds aresuitable for treating the following diseases: respiratory disorders suchas chronic obstructive pulmonary disease(COPD), chronic bronchitis,bronchial hyperreactivity, asthma and rhinitis; urological disorderssuch as urinary incontinence, pollakinuria in neuripenia pollakinuria,neurogenic or unstable bladder, cystospasm and chronic cystitis; andgastrointestinal disorders such as irritable bowel syndrome, spasticcolitis, diverticulitis and peptic ulceration.

The compounds claimed are also useful for the treatment of therespiratory diseases detailed above in association with β₂ agonists,steroids, antiallergic drugs or phosphodiesterase IV inhibitors.

Compounds of the present invention may also be expected to haveanti-tussive properties.

Depending on their nature the new compounds may be suitable for treatingvagally induced sinus bradycardia.

Compounds with related structures have been described as anti-spasmodicsand anti-cholinergic agents in several patents.

For example, in patent FR 2012964 are described quinuclidinolderivatives of the formula:

in which R is H, OH or an alkyl group having 1 to 4 carbon atoms; R₁ isa phenyl or thienyl group; and R₂ is a cyclohexyl, cyclopentyl orthienyl group, or, when R is H, R₁ and R₂ together with the carbon atomto which they are attached, form a tricyclic group of the formula:

in which X is —O—, —S— or —CH₂—, or an acid addition or quaternaryammonium salt thereof.

EP-418716 describes thienyl carboxylate esters of formula

wherein A is a group

m and n=1 or 2Q is a —CH₂—CH₂—, —CH₂—CH₂—CH₂—, —CH═CH—, group

Q′ is a ═NR or NRR═ group; R₁ is a thienyl, phenyl, furyl, cyclopentylor cyclohexyl group, optionally substituted; R₂ is H, OH, C₁-C₄ alkoxyor C₁-C₄ alkyl and R_(a) is H, F, Cl, CH₃— or —NR.

U.S. Pat. No. 5,654,314 describes compounds of formula:

wherein R is an optionally halo- or hydroxy-substituted C₁₋₄ alkylgroup; R is a C₁₋₄ alkyl group; or R and R═ together form a C₄₋₆alkylene group; X⁻ is an anion; and R₁ is H, OH, —CH₂OH, C₁₋₄ alkyl orC₁₋₄ alkoxy.

The present invention provides new quinuclidine derivatives with potentantagonist activity at muscarinic M₃ receptors which have the chemicalstructure described in formula (I):

wherein:

-   Ĉ is a phenyl ring, a C₄ to C₉ heteroaromatic group containing one    or more heteroatoms (preferably selected from nitrogen, oxygen and    sulphur atoms), or a naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl or    biphenyl group;-   R¹, R² and R³ each independently represent a hydrogen or halogen    atom, or a hydroxy group, or a phenyl, —OR⁴, —SR⁴, —NR⁴R⁵, —NHCOR⁴,    —CONR⁴R⁵, —CN, —NO₂, —COOR⁴ or —CF₃ group, or a straight or branched    lower alkyl group which may optionally be substituted, for example,    with a hydroxy or alkoxy group, wherein R⁴ and R⁵ each independently    represent a hydrogen atom, straight or branched lower alkyl group,    or together form an alicyclic ring; or R¹ and R² together form an    aromatic, alicyclic or heterocyclic ring;-   n is an integer from 0 to 4;-   A represents a —CH₂—, —CH═CR⁶—, —CR⁶═CH—, —CR⁶R⁷—, —CO—, —O—, —S—,    —S(O)—, SO₂ or —NR⁶— group, wherein R⁶ and R⁷ each independently    represent a hydrogen atom, straight or branched lower alkyl group,    or R⁶ and R⁷ together form an alicyclic ring;-   m is an integer from 0 to 8; provided that when m=0, A is not —CH₂—;-   p is an integer from 1 to 2 and the substitution in the    azoniabicyclic ring may be in the 2, 3 or 4 position including all    possible configurations of the asymmetric carbons;-   B represents a group of formula i) or ii):

wherein R¹⁰ represents a hydrogen atom, a hydroxy or methyl group; andR⁸ and R⁹ each independently represents

wherein R¹¹ represents a hydrogen or halogen atom, or a straight orbranched lower alkyl group and Q represents a single bond, —CH₂—,—CH₂—CH₂—, —O—, —O—CH₂—, —S—, —S—CH₂— or —CH═CH—; and when i) or ii)contain a chiral centre they may represent either configuration; Xrepresents a pharmaceutically acceptable anion of a mono or polyvalentacid.

In the quaternary ammonium compounds of the present inventionrepresented by formula (I) an equivalent of an anion (X⁻) is associatedwith the positive charge of the N atom. X⁻ may be an anion of variousmineral acids such as, for example, chloride, bromide, iodide, sulfate,nitrate, phosphate, and organic acids such as, for example, acetate,maleate, fumarate, citrate, oxalate, succinate, tartrate, malate,mandelate, methanesulfonate and p-toluenesulfonate. X⁻ is preferably ananion selected from chloride, bromide, iodide, sulphate, nitrate,acetate, maleate, oxalate or succinate. More preferably X⁻ is chloride,bromide or trifluoroacetate.

The compounds of the present invention represented by the formula (I)described above, which may have one or more assymetric carbons, includeall the possible stereoisomers. The single isomers and mixtures of theisomers fall within the scope of the present invention.

If any of R¹ to R⁷ or R¹¹ represents an alkyl group, it is preferredthat said alkyl group contains 1 to 8, preferably 1 to 6 and morepreferably 1 to 4 carbon atoms. In particular it is preferred that anyalkyl group is represented by a methyl, ethyl, propyl, includingi-propyl, butyl including a n-butyl, sec-butyl and tert-butyl.

The alicyclic and heterocyclic rings mentioned in relation to formula(I) preferably comprise from 3 to 10, preferably from 5 to 7 members.The aromatic rings mentioned in relation to formula (I) above preferablycontain from 6 to 14, preferably 6 or 10 members.

Preferred compounds of formula (I) are those wherein Ĉ represents aphenyl, pyrrolyl, thienyl, furyl, biphenyl, naphthalenyl,5,6,7,8-tetrahydronaphthalenyl, benzo[1,3]dioxolyl, imidazolyl orbenzothiazolyl group, in particular a phenyl, pyrrolyl, or thienylgroup; R¹, R² and R³ each independently represent a hydrogen or halogenatom, or a hydroxyl, methyl, tert-butyl, —CH₂OH, 3-hydroxypropyl, —OMe,—NMe₂, —NHCOMe, —CONH₂, —CN, —NO₂, —COOMe or —CF₃ group, in particular ahydrogen atom, a hydroxy group or a halogen atom, wherein the halogenatom is preferably fluorine; n=0 or 1; m is an integer from 1 to 6,particularly 1, 2 or 3; A represents a —CH₂—, —CH═CH—, —CO—, —NH—,—NMe-, —O— or —S— group, in particular a —CH₂—, —CH═CH— or —O— group.

It is also preferred that p=2 and the substituent group —OC(O)B attachedto the azoniabicyclo[2.2.2]octane is at the 3 position, preferablyhaving the (R) configuration.

Further preferred compounds of formula I are those wherein B is a groupof formula i) or ii) as defined above wherein, if B is a group offormula (i), R⁸ and R⁹ each independently represent a phenyl, 2-thienyl,3-thienyl, 2-furyl or 3-furyl group, wherein R¹¹ is hydrogen atom; and,if B is a group of formula (ii), Q represents a single bond, —CH₂—,—CH₂—CH₂—, —O— or —S— group, in particular a single bond, —CH₂—,—CH₂—CH₂— or —O— group, most preferably a single bond or —O— group; andin any case R¹⁰ is a hydrogen atom or a hydroxy or methyl group; andwhen i) or ii) contain a chiral centre they may represent either the (R)or the (S) configuration.

Most preferably the —OC(O)B group in formula (I) is diphenylacetoxy,2-hydroxy-2,2-diphenyl-acetoxy, 2,2-diphenylpropionyloxy,-hydroxy-2-phenyl-2-thien-2-yl-acetoxy,2-furan-2-yl-2-hydroxy-2-phenylacetoxy, 2,2-dithien-2-ylacetoxy,2-hydroxy-2,2-di-thien-2-ylacetoxy, 2-hydroxy-2,2-di-thien-3-ylacetoxy,9-hydroxy-9[H]-fluorene-9-carbonyloxy,9-methyl-9[H]-fluorene-9-carbonyloxy, 9[H]-xanthene-9-carbonyloxy,9-hydroxy-9[H]-xanthene-9-carbonyloxy,9-methyl-9[H]-xanthene-9-carbonyloxy,2,2-bis(4-fluorophenyl)-2-hydroxyacetoxy,2-hydroxy-2,2-di-p-tolylacetoxy, 2,2-difuran-2-yl-2-hydroxyacetoxy,2,2-dithien-2-ylpropionyloxy, 9,10-dihydroanthracene-9-carbonyloxy,9[H]-thioxanthene-9-carbonyloxy, or5[H]-dibenzo[a,d]cycloheptene-5-carbonyloxy. Especially preferredcompounds are those wherein the —OC(O)B group in formula (I) isdiphenylacetoxy, 2-hydroxy-2,2-diphenyl-acetoxy,2,2-diphenylpropionyloxy, 2-hydroxy-2-phenyl-2-thien-2-yl-acetoxy,2-furan-2-yl-2-hydroxy-2-phenylacetoxy, 2,2-dithien-2-ylacetoxy,2-hydroxy-2,2-di-thien-2-ylacetoxy, 2-hydroxy-2,2-di-thien-3-ylacetoxy,9-hydroxy-9[H]-fluorene-9-carbonyloxy,9-methyl-9[H]-fluorene-9-carbonyloxy, 9[H]-xanthene-9-carbonyloxy,9-hydroxy-9[H]-xanthene-9-carbonyloxy or9-methyl-9[H]-xanthene-9-carbonyloxy.

The most preferred compounds of formula (I) are those wherein theazoniabicyclo group is substituted on the nitrogen atom with a3-phenoxypropyl, 2-phenoxyethyl, 3-phenylallyl, phenethyl,4-phenylbutyl, 3-phenylpropyl, 3-[2-hydroxyphenoxy]propyl,3-[4-fluorophenoxy]propyl, 2-benzyloxyethyl, 3-pyrrol-1-ylpropyl,2-thien-2-ylethyl, 3-thien-2-ylpropyl, 3-phenylaminopropyl,3(methylphenylamino)propyl, 3-phenylsulfanylpropyl, 3-o-tolyloxypropyl,3-(2,4,6-trimethylphenoxy)propyl,3-(2-tert-butyl-6-methylphenoxy)propyl, 3-(biphenyl-4-yloxy)propyl,3-(5,6,7,8-tetrahydronaphthalen-2-yloxy)-propyl,3-(naphthalen-2-yloxy)propyl, 3-(naphthalen-1-yloxy)propyl,3-(2-chlorophenoxy)propyl, 3-(2,4-difluorophenoxy)propyl,3-(3-trifluoromethylphenoxy)propyl, 3-(3-cyanophenoxy)propyl,3-(4-cyanophenoxy)propyl, 3-(3-methoxyphenoxy)propyl,3-(4-methoxyphenoxy)propyl, 3-(benzo[1,3]dioxol-5-yloxy)propyl,3-(2-carbamoylphenoxy)propyl, 3-(3-dimethylaminophenoxy)propyl,3-(4-nitrophenoxy)propyl, 3-(3-nitrophenoxy)propyl,3-(4-acetylaminophenoxy)propyl, 3-(3-methoxycarbonylphenoxy)propyl,3-[4-(3-hydroxypropyl)phenoxy]propyl, 3-(2-hydroxymethylphenoxy)propyl,3-(3-hydroxymethylphenoxy)propyl, 3-(4-hydroxymethylphenoxy)propyl,3-(2-hydroxyphenoxy)propyl, 3-(4-hydroxyphenoxy)propyl,3-(3-hydroxyphenoxy)propyl, 4-oxo-4-thien-2-ylbutyl,3-(1-methyl-[1H]-imidazol-2-ylsulfanyl)propyl,3-(benzothiazol-2-yloxy)propyl, 3-benzyloxypropyl,6-(4-phenylbutoxy)hexyl, 4-phenoxybutyl, or 2-benzyloxyethyl group.Especially preferred compounds are those wherein the azoniabicyclo groupis substituted on the nitrogen atom with a 3-phenoxypropyl,2-phenoxyethyl, 3-phenylallyl, phenethyl, 4-phenylbutyl, 3-phenylpropyl,3-[2-hydroxyphenoxy]propyl, 3-[4-fluorophenoxy]propyl, 2-benzyloxyethyl,3-pyrrol-1-ylpropyl, 2-thien-2-ylethyl or 3-thien-2-ylpropyl group.

The following compounds are intended to illustrate but not to limit thescope of the present invention.

-   3(R)-Diphenylacetoxy-1-(3-phenoxy-propyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   3(R)-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   3(R)-(2,2-Diphenylpropionyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   3(R)-(2-Hydroxy-2-phenyl-2-thien-2-yl-acetoxy)-1-(3-phenoxypropyl)-1-azonia-bicyclo[2.2.2]octane;    bromide-   3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   3(R)-(2,2-Dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azonia-bicyclo[2.2.2]octane;    bromide-   3(R)-(2-Hydroxy-2,2-di-thien-2-ylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane;    bromide-   3(R)-(2-Hydroxy-2,2-di-thien-2-ylacetoxy)-1-(4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azonia-bicyclo[2.2.2]octane;    bromide-   1-[3-(4-Fluorophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo-[2.2.2]octane;    chloride-   3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(2-hydroxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;    trifluoroacetate-   3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-pyrrol-1-ylpropyl)-1-azonia-bicyclo[2.2.2]octane;    trifluoroacetate-   3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(2-thien-2-ylethyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   3(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   1-(2-Benzyloxyethyl)-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane;    trifluoroacetate-   3(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   1-(3-phenylallyl)-3(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;    bromide-   3(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   3(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane;    bromide-   3(R)-(9-Hydroxy-9H-fluorene-9-carbonyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   3(R)-(9-Methyl-9[H]-fluorene-9-carbonyloxy)-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   3(R)-(9-Methyl-9[H]-fluorene-9-carbonyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   1-(4-Phenylbutyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;    bromide-   1-(2-Phenoxyethyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;    bromide-   1-(3-Phenoxypropyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;    bromide-   1-Phenethyl-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;    bromide-   3(R)-(9-Hydroxy-9[H]-xanthene-9-carbonyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   3(R)-(9-Hydroxy-9[H]-xanthene-9-carbonyloxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane;    bromide-   3(R)-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane;    bromide-   3(R)-(9-Methyl-9[H]-xanthene-9-carbonyloxy)-1-(3-phenoxy-propyl)-1-azonia-bicyclo[2.2.2]octane;    bromide

The present invention also provides processes for preparing compounds offormula (I).

The quaternary ammonium derivatives of general Formula I, may beprepared by reaction of an alkylating agent of general Formula II withcompounds of general Formula III. In Formulas I, II and III, R¹, R², R³,Ĉ, A, X, B, n, m and p are as defined above.

This alkylation reaction may be carried out by two differentexperimental procedures, a) and b)which are described-below. Inparticular method b) provides a new experimental process, using solidphase extraction methodologies, that allows the parallel preparation ofseveral compounds. Methods a) and b) are described in the experimentalsection. Compounds of general Formula II which are not commerciallyavailable have been prepared by synthesis according to standard methods.For example, compounds wherein n=0 and A=—O—, —S— or —NR⁶, wherein R⁶ isas defined above, were obtained by reaction of the correspondingaromatic derivative or its potassium salt with an alkylating agent ofgeneral formula Y—(CH₂)m-X, wherein X may be a halogen and Y may be ahalogen or a sulphonate ester. In other examples, compounds of generalFormula II, where n>=1 were synthesised from the corresponding alcoholderivative of general Formula IV by known methods.

Compounds of general Formula III may be prepared by three differentmethods c, d and e illustrated in the following scheme and detailed inthe experimental section.

Some compounds of general formula III where B is a group of formula i),R⁸ and R⁹ are as described above and R¹⁰ is a hydroxy group, may also beprepared from the glyoxalate esters of general formula VII by reactionwith the corresponding organometallic derivative.

Compounds of general formula VII may be prepared from the correspondingglyoxylic acids following the standard methods c, d and e describedabove and detailed in the experimental section. The glyoxalatederivatives of formula VII where R⁸ is a 2-thienyl or 2-furyl group havenot been described before.

The following compounds are examples of compounds of general formula IIIand VII which have not been described before:

-   9-Methyl-9[H]-fluorene-9-carboxylic acid    1-azabicyclo[2.2.2]oct-3(R)-yl ester (intermediate I-1c).;-   9-Methyl-9[H]-xanthene-9-carboxylic acid    1-azabicyclo[2.2.2]oct-3(R)-yl ester (intermediate I-1d);-   2-Hydroxydithien-2-yl-acetic acid 1-azabicyclo[2.2.2]oct-4-yl ester    (intermediate I-4a).-   Oxothien-2-yl-acetic acid 1-azabicyclo[2.2.2]oct-4-yl ester    (intermediate I-4b).-   Oxothien-2-yl-acetic acid 1-azabicyclo[2.2.2]oct-3(R)-yl ester    (intermediate I-4g).-   Oxofuran-2-yl-acetic acid 1-azabicyclo[2.2.2]oct-3(R)-yl ester    (intermediate I-4e).-   2-Hydroxy-2,2-difuran-2-yl-acetic acid    1-azabicyclo[2.2.2]oct-3(R)-yl ester (intermediate I-4d).

Compounds of Formula V could be:

-   4-hydroxy-1-azabicyclo[2.2.1]heptane, described in WO150080-   4-hydroxy-1-azabicyclo[2.2.2]octane, described in Grob, C. A. et.al.    Helv. Chim. Acta (1958), 41, 1184-1190-   3(R)-hydroxy-1-azabicyclo[2.2.2]octane or    3(S)-hydroxy-1-azabicyclo[2.2.2]octane, described in Ringdahl, R.    Acta Pharm Suec. (1979), 16, 281-283 and commercially available from    CU Chemie Uetikon GmbH.

The following examples are intended to illustrate, but not to limit, theexperimental procedures that have been described above.

The structures of the prepared compounds were confirmed by ¹HNMR and MS.The NMR were recorded using a Varian 300 MHz instrument and chemicalshifts are expressed as parts per million (δ) from the internalreference tetramethyl silane. Their purity was determined by HPLC, usingreverse phase chromatrography on a Waters instrument, with valuesgreater than 95% being obtained. Molecular ions were obtained byelectrospray ionization mass spectometry on a Hewlett Packardinstrument.

Method - a -

EXAMPLE 20 Preparation of 3(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane, bromide

200 mg of (Furan-2-yl)-hydroxy-phenylacetic acid1-aza-bicyclo[2.2.2]oct-3(R)-yl ester (0.6 mmol) were suspended in 4 mlof CH3CN and 6 ml of CHCl3. To this suspension were added 0.48 ml (3mmol) of 3-phenoxypropyl bromide. After stirring for 72 h at roomtemperature in inert atmosphere, solvents were evaporated. Ether wasadded and the mixture stirred. The solid obtained was filtered andwashed several times with ether. The yield was 0.27 g (83%) of titlecompound as a mixture of diastereomers.

¹H-NMR (DMSO-d6): δ 1.50-2.20 (m, 6H), 2.25 (m, 1H), 3.10 (m, 1H),3.20-3.60 (m, 6H), 3.95 (m, 1H), 4.05 (m, 2H), 5.20 (m, 1H), 6.25-6.35(double dd, 1H), 6.45 (m, 1H), 6.95 (m, 4H), 7.30-7.50 (m, 7H), 7.70 (m,1H); MS [M-Br]⁺: 462; mp 166° C.

Method - b -

EXAMPLE 51 Preparation of 3(R)-(2-Hydroxy-2,2-di-thien-2-ylacetoxy)-1-[3-(naphthalen-1-yloxy)propyl]-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

60 mg (0.17 mmols) of hydroxy-dithien-2-yl-acetic acid1-aza-bicyclo[2.2.2]oct-3(R)-yl ester were dissolved in 1 ml of dmso. Tothis solution 188 mg (0.85 mmol) of 3-(naphthalen-1-yloxy)-propylchloride were added. After stirring overnight at room temperature, themixture was purified by solid phase extraction with a cation exchangeMega Bond Elut cartridge, previously conditioned at pH=7.5 with 0.1 MNaH2PO4 buffer. The reaction mixture was applied to the cartridge andwashed first with 2 ml of DMSO and then three times with 5 ml of CH3CN,rinsing away all starting materials. The ammonium derivative was elutedwith 5 ml of 0.03 M TFA solution in CH3CN:CHCl3 (2:1). This solution wasneutralized with 300 mg of poly(4-vinylpyridine), filtered andevaporated to dryness.

The yield was 17 mg (15%) of title compound. ¹H-NMR (DMSO-d6): δ 1.7-2.1(m, 4H), 2.2-2.4 (m, 3H), 3.2-3.6 (m, 7H), 4.0 (m, 1H), 4.2 (t, 2H),5.25 (m, 1H), 7.0 (m 3H), 7.2 (m, 2H), 7.4-7.6 (m, 7H), 7.85 (d, 1H),8.2 (d, 1H); MS [M-CF₃COO]⁺: 534.

Method - c -

Methyl ester derivatives of general Formula VI were prepared by standardmethods of esterification from the corresponding carboxylic acid orfollowing the procedures described in examples I-1e, I-1f and I-1g oraccording to procedures described in literature: FR 2012964; Larsson. Let al. Acta Pharm. Suec. (1974), 11(3), 304-308; Nyberg, K. et.al. ActaChem. Scand. (1970), 24, 1590-1596; and Cohen, V. I. et.al. J. Pharm.Sciences (1992), 81, 326-329.

EXAMPLE I-1a Preparation of (Furan-2-yl)hydroxyphenylacetic acid1-azabicyclo[2.2.2]oct-3(R)-yl ester

3.24 g (0.014 mols) of (Furan-2-yl)-hydroxy-phenylacetic acid methylester were dissolved in 85 ml of toluene. To this solution were added2.08 g (0.016 mols) of 3-(R)-hydroxy-1-azabicyclo[2.2.2]octane and 0.224g (5.6 mmols) of HNa (60% dispersion in mineral oil). The mixture wasrefluxed with continuous removal of distillate and when necessaryreplacement with fresh toluene for 1.5 hours. The cooled mixture wasextracted with 2N HCl acid, the aqueous layer washed with ethyl acetate,basified with K2CO3 and extracted with CHCl3. The organic layer wasdried over Na2SO4 and evaporated. The oil obtained (3.47 g) crystallisedafter cooling at room temperature. This solid was suspended in hexaneand filtered. The yield was 2.5 g (54%) of a mixture of diasteroisomers,mp: 140-142° C.;GC/MS [M]⁺: 327; ¹H-NMR (CDCl3): δ 1.20-1.70 (m, 4H),1.90-2.10 (m, 1H), 2.45-2.80 (m, 5H), 3.10-3.30 (m, 1H), 4.8 (bs, OH),4.90-5.0 (m, 1H), 6.20 (m, 1H), 6.35 (m, 1H), 7.30-7.50 (m, 4H),7.60-7.70 (m, 2H).

After four crystallizations of 0.5 g of this mixture from boilingacetonitrile, 0.110 g of a pure diastereomer(1) were obtained. From themother liquors of crystallization was obtained the other diastereomer(2). (*: configuration not assigned). Diastereomer 1 was hydrolysed toyield (+)-2-hydroxy-2-phenyl-2-furan-2-ylacetic acid as a pureenantiomer, [α]²⁵ _(D)=+5.6 (c=2, EtOH). Diastereomer 2 was hydrolysedto yield (−)-2-hydroxy-2-phenyl-2-furan-2-ylacetic acid as a pureenantiomer, [α]²⁵ _(D)=−5.7 (c=2, EtOH).

Diastereomer 1: 2(*)-(Furan-2-yl)hydroxyphenylacetic acid1-azabicyclo[2.2.2]oct-3(R)-yl ester. ¹H-NMR (CDCl3): δ 1.20-1.70 (m,4H), 1.90 (m, 1H), 2.45-2.50 (m, 1H), 2.50-2.80 (m, 4H), 3.10-3.20 (m,1H), 4.8 (bs, OH), 4.90-5.0 (m, 1H), 6.20 (m, 1H), 6.35 (m, 1H),7.30-7.50 (m, 4H), 7.60-7.70 (m, 2H).

Diastereomer 2:2(*)-(Furan-2-yl)hydroxyphenylacetic acid1-azabicyclo[2.2.2]oct-3(R)-yl ester. ¹H-NMR (CDCl3): δ 1.20-1.70 (m,4H), 2.10 (m, 1H), 2.50-2.80 (m, 5H), 3.20-3.30 (m, 1H), 4.8 (bs, OH),4.90-5.0 (m, 1H), 6.20 (m, 1H), 6.35 (m, 1H), 7.30-7.50 (m, 4H),7.60-7.70 (m, 2H).

EXAMPLE I-1b Preparation of Furan-2-ylhydroxythien-2-ylacetic acid1-azabicyclo[2.2.2]oct-3(R)-yl ester

Prepared as in example I-1a. The yield was 3.06 g (64.3%) of a mixtureof diastereoisomers, mp: 1721 C; GC/MS [M]⁺: 333; ¹H-NMR (DMSO-d6): δ1.21-1.27 (m, 1H), 1.41-1.60 (m, 3H), 1.87 (m, 1H), 2.36-2.69 (m, 5H),3.02-3.14 (m, 1H), 4.75-4.82 (m, 1H), 6.24-6.25 (m, 1H), 6.42-6.45 (m,1H), 7.01-7.06 (m, 1H), 7.11-7.14 (m, 2H), 7.51-7.54 (m, 1H), 7.66-7.69(m, 1H).

EXAMPLE I-1c Preparation of 9-Methyl-9[H]-fluorene-9-carboxylic acid1-azabicyclo[2.2.2]oct-3(R)-yl ester

Prepared as in example I-1a. The yield was 3.34 g of an oil (80%). Thisproduct was solidified by formation of the oxalate salt (1:1), mp: 1861C. MS [M free base+1]⁺: 334. Oxalate salt, ¹H-NMR (DMSO-d6): δ 1.43-1.55(m, 2H), 1.68-1.78 (m, 2H), 1.75 (s, 3H), 2.02 (m, 1H), 2.70-2.90 (m,1H), 2.92-3.15 (m, 4H), 3.50-3.57 (m, 1H), 4.88 (m, 1H), 7.35-7.47 (m,4H), 7.62-7.70 (m, 2H), 7.89-7.91 (m, 2H).

EXAMPLE I-1d Preparation of 9-Methyl-9[H]-xanthene-9-carboxylic acid1-azabicyclo[2.2.2]oct-3(R)-yl ester

Prepared as in example I-1a. The yield was 1.91 g of an oil (53%). Thisproduct was solidified by formation of the oxalate salt (1:1), mp: 1521C. MS [M free base+1]⁺: 350. Oxalate salt, ¹H-NMR (DMSO-d6): δ 1.20-1.30(m, 1H), 1.40-1.52 (m, 1H), 1.64-1.81 (m, 2H), 1.90 (s, 3H), 2.0 (m,1H), 2.53-2.66 (m, 1H), 2.71-2.76 (m, 1H), 2.97-3.10 (m, 3H), 3.44-3.52(m, 1H), 4.90-4.92 (m, 1H), 7.12-7.18 (m, 4H), 7.32-7.38 (m, 2H),7.43-7.48 (m, 2H), 8.0-9.8 (bs, 1H, H⁺).

EXAMPLE I-1e Preparation of 9-Methyl-9[H]-fluorene-9-carboxylic acidmethyl ester

Lithium diisopropylamide (26.7 ml of a 2M solution inheptane/tetrahydrofurane/ethylbenzene, 0.053 mol) was added to a stirredsolution of 9[H]-fluorene-9-carboxylic acid (5 g, 0.0237 mol) in THF (70ml) at between 0 and 51 C in N₂ atmosphere. The mixture was warmed toroom temperature and refluxed 1.5 hours. The reaction mixture was cooledto room temperature and a solution of CH3I (1.85 ml, 0.03 mol) in THF(1.85 ml) was added. The mixture was stirred overnight at roomtemperature and evaporated. To the residue in MeOH (70 ml) was addedconcentrated sulfuric acid (3.9 ml) in MeOH (25 ml), the mixture wasrefluxed for 2 hours and evaporated. The residue was partitioned betweenchloroform and saturated K2CO3 solution. The aqueous layer was extractedagain with chloroform and the organic layers were combined, washed withwater, dried over sodium sulphate and evaporated to dryness to obtain5.73 g of a brown oil. This product was purified by columnchromatography (silica gel, hexane/ethyl acetate 95:5) to yield 4.43 g(78.5%) of a pure product, structure confirmed by ¹H-NMR.

¹H-NMR (CDCl3): δ 1.80 (s, 3H), 3.60 (s, 3H), 7.50-7.65 (m, 4H), 7.75(m, 2H), 8.0 (m, 2H).

EXAMPLE I-1f Preparation of 9-Methyl-9[H]-xanthene-9-carboxylic acidmethyl ester

Prepared as in example I-1e. The yield was 2.65 g (47.2%). ¹H-NMR(CDCl3): δ 1.90 (s, 3H), 3.6 (s, 3H), 7.05-7.35 (m, 8H).

EXAMPLE I-1g Preparation of 9-Hydroxy-9[H]-xanthene-9-carboxylic acidmethyl ester

Lithium diisopropylamide (20.3 ml of a 2M solution inheptane/tetrahydrofurane/ethylbenzene, 0.041 mol) was added to a stirredsolution of 7 g (0.029 mol) of 9[H]-xantene-9-carboxylic acid methylester (prepared by a standard method) in THF (70 ml) at between 0 and 51C in N₂ atmosphere. The mixture was stirred 1 h at this temperature andthen was added by N2 pressure to a dry solution of oxygen in ether at 01C. After 30 min, an equal volum of NaHSO3, 40% aqueous solution, wasadded, and the reaction mixture was warmed to room temperature andstirred for 30 min. The two layers were separated and the aqueous phasewas extracted twice with ethyl acetate. The organic phases werecombined, treated with NaHSO3 (40% aqueous solution), washed with water,dried over-sodium sulphate and evaporated to dryness to obtain 8.89 g ofa brown solid.

This procedure was repeated with 5 g of starting material yielding 6.04g of the same brown solid.

The products were combined and purified by column chromatography (silicagel, hexane/ethyl acetate 90:10) to yield 7.60 g (global Rt: 59.4%) of apure product, structure confirmed by ¹H-NMR.

¹H-NMR (DMSO-d6): δ 3.5 (s, 3H), 7.0 (s, 1H, OH), 7.2 (m, 4H), 7.4 (m,2H), 7.55 (m, 2H).

Method - d -

EXAMPLE I-2a Preparation of10,11-Dihydro-5[H]-dibenzo[a,d]cycloheptane-5-carboxylic acid1-azabicyclo[2.2.2]oct-3-(R)-yl ester

2.15 g of 10,11-Dihydro-5[H]-dibenzo[a,d]cycloheptane-5-carboxylic acid(9.0 mmol) were dissolved in 40 ml of CHCl3 (ethanol free). The solutionwas cooled at 0° C. and 0.86 ml of oxalyl chloride (9.9 mmols) and adrop of DMF were added. The mixture was stirred and allowed warm to roomtemperature. After an hour at this temperature the solvents wereevaporated and the residue was dissolved in CHCl3 and evaporated again.This procedure was repeated two times. The obtained oil was dissolved in20 ml of toluene and added to a solution of 1.26 g (9.9 mmol) of3(R)-hydroxy-1-azabicyclo[2.2.2]octane in 40 ml of hot toluene. Thereaction mixture was refluxed for 2 hours. After cooling the mixture wasextracted with 2N HCl acid. The aqueous layer was basified with K2CO3and extracted with CHCl3. The organic layer was dried over Na2SO4 andevaporated to dryness. The residue was purified by column chromatography(silica gel, CHCl3:MeOH:NH4OH, 95:5:0.5). The yield was 1.5 g (48%); mp:112-113° C.; CG/MS [M]⁺: 347; ¹H-NMR (CDCl3): δ 1.10-1.35 (m, 2H),1.40-1.52 (m, 1H), 1.52-1.68 (m, 1H), 1.90 (m, 1H), 2.40-2.60 (m, 2H),2.60-2.77 (m, 3H), 2.83-2.96 (m, 2H), 3.07-3.19 (m, 1H), 3.25-3.40 (m,2H), 4.80 (m, 2H), 7.10-7.30 (m, 8H).

10,11-Dihydro-5[H]-dibenzo[a,d]cycloheptane-5-carboxylic acid wasprepared as described in Kumazawa T. et al., J. Med. Chem., (1994), 37,804-810.

EXAMPLE I-2b Preparation of 5[H]-Dibenzo[a,d]cycloheptene-5-carboxylicacid 1-azabicyclo[2.2.2]oct-3-(R)-yl ester

Prepared as in example I-2a. The yield was 3.12 g (71%); mp 1291 C; MS[M+1]⁺: 346; ¹H-NMR (DMSO-d6): δ 0.90-1.10 (m, 2H), 1.30-1.50 (m, 2H),1.58 (m, 1H), 2.21-2.26 (m, 2H), 2.47-2.50 (m, 3H), 2.86-2.94 (m, 1H),4.48-4.51 (m, 1H), 5.33 (s, 1H), 7.0 (m, 2H), 7.29-7.43 (m, 6H),7.49-7.51 (m, 2H).

5[H]-Dibenzo[a,d]cycloheptene-5-carboxylic acid was prepared asdescribed in M. A. Davis et al; J. Med. Chem., (1964), Vol 7, 88-94.

EXAMPLE I-2c Preparation of 9,10-Dihydroanthracene-9-carboxylic acid1-azabicyclo[2.2.2]oct-3-(R)-yl ester

Prepared as in example I-2a. The yield was 0.77 g (62.6%); mp 1391 C; MS[M+1]⁺: 334; ¹H-NMR (DMSO-d6): δ 1.1-1.2 (m, 1H), 1.25-1.40 (m, 2H),1.40-1.55 (m, 1H), 1.73 (m, 1H), 2.20 (m, 1H), 2.35-2.65 (m, 4H),2.90-2.98 (m, 1H), 3.93-4.14 (dd, 2H, J=1.8 Hz, J=4.3 Hz), 4.56 (m, 1H),5.14 (s, 1H), 7.25-7.35 (m, 4H), 7.35-7.50 (m, 4H).

9,10-Dihydro-anthracene-9-carboxylic acid was prepared as described inE. L. May and E. Mossettig; J. Am. Chem. Soc., (1948), Vol 70, 1077-9.

Method - e -

EXAMPLE I-3 Preparation of 2,2-Diphenylpropionic acid1-azabicyclo-[2.2.2]oct-3(R)-yl ester

1.1 g (4.8 mmol) of 2,2-diphenylpropionic acid were dissolved in 20 mlof THF. To this solution were added 0.87 g (5.3 mmol) of1,1=-carbonyldiimidazole and the mixture was refluxed for an hour. Thereaction was monitored by TLC following the formation of theimidazolide. When the reaction was completed part of the solvent wasevaporated and 0.67 g (5.3 mmol) of3-(R)-hydroxy-1-azabicyclo[2.2.2]octane were added. The reaction mixturewas refluxed for 16 h, cooled, diluted with ether and washed with water.The organic layer was extracted with HCl 2N, the acid solution basifiedwith K2CO3 and extracted with CHCl3. The organic solution was dried overNa2SO4 and evaporated to dryness to yield 1.21 g (75.2%) of an oil thatwas identified as the title ester.

0.64 g (1.9 mmol) of 2,2-Diphenylpropionic acid 1-azabicyclo[2.2.2]oct-3(R)-yl ester were dissolved in 6 ml of ketone and 0.085 g(0.95 mmol) of oxalic acid were added. After slow addition of ether awhite solid was formed. The yield was 0.33 g (45.6%) of oxalate of2,2-Diphenyl-propionic acid 1-azabicyclo[2.2.2]oct-3(R)-yl ester; mp:1461 C; MS [M free base+1]⁺: 336.

Oxalate salt, ¹H-NMR (CDCl3): δ 1.40-1.64 (m, 2H), 1.90 (s, 3H),1.80-2.0 (m, 2H), 2.31 (m, 1H), 2.73-2.85 (m, 1H), 3.0-3.10 (m, 1H),3.10-3.32 (m, 3H), 3.53-3.70 (m, 1H), 5.13 (m, 1H), 7.14-7.40 (m, 10H),9.25 (broad band, 2H, H⁺).

Method - f -

EXAMPLE I-4a Preparation of 2-Hydroxy-2,2-dithien-2-ylacetic acid1-azabicyclo[2.2.2]oct-4-yl ester

A solution of 2-thienylmagnesium bromide was prepared from 220 mg (9mmols) of Magnesium and 0.86 ml (9 mmols) of 2-bromothiophene in 15 mlof THF. This solution was added to 1.95 g (7 mmols) ofoxothien-2-yl-acetic acid 1-azabicyclo[2.2.2]oct-4-yl ester(intermediate I-4b) dissolved in 20 ml of THF. The mixture was stirredat room temperature for 1 hour, refluxed for 1 hour, cooled, treatedwith a saturated solution of ammonium chloride and extracted with ether.After removal of the solvent the solid obtained was recrystallised fromacetonitrile to yield 1.45 g, of a white solid (56%). ¹H-NMR (DMSO-d6):δ 1.80-2.0 (m, 6H), 2.80-3.0 (m, 6H), 7.0 (m, 2H), 7.13 (m, 2H), 7.18(s, 1H), 7.51 (m, 2H); MS [M+1]: 350; mp 174° C.

EXAMPLE I-4b Preparation of oxothien-2-yl-acetic acid1-azabicyclo[2.2.2]oct-4-yl ester

Oxalyl chloride (1.5 ml, 0.017 mol) was added to a solution ofoxothien-2-yl-acetic acid (2.24 g, 0.014 mol) and dimethylformamide (onedrop) in 30 ml of chloroform (etanol free) at 01 C. The mixture wasstirred and allowed to warm at room temperature. After one hour thesolvent was evaporated. The residue was dissolved in chloroform andevaporated again. This procedure was repeated two times. The productobtained was disolved in CHCl3 (30 ml) and added to a suspension of 1.1g (0.009 mols) of 4-hydroxy-1-azabicyclo[2.2.2]octane, 1.8 ml oftriethylamine (0.013 mols), 0.6 g (0.9 mmols) ofN-(methylpolystyrene)-4-(methylamino) pyridine at 70° C. The mixture wasrefluxed for 1 hour, cooled, filtered and washed with water. The titleproduct was extracted with a solution of diluted HCl, washed with CHCl3,basified with K2CO3 and extracted again with CHCl3. After removal of thesolvent 1.47 g (45%) of a solid was obtained. ¹H-NMR (dmso): δ 2.0 (m,6H), 2.9 (m, 6H), 7.35 (m, 1H), 8.05 (m, 1H), 8.3 (m, 1H).

EXAMPLE I-4c Preparation of (Furan-2-yl)hydroxyphenylacetic acid1-azabicyclo[2.2.2]oct-3(R)-yl ester

Phenylmagnesium bromide, 0.0057 mol (5.7 ml of a solution 1M in THF),was added to a solution of 1.3 g (0.0052 mol) of oxofuran-2-ylaceticacid 1-azabicyclo[2.2.2]oct-3(R)-yl ester (intermediate I-4e-) dissolvedin 15 ml of THF, at −701 C in N2 atmosphere. The mixture was stirred atthis temperature for 10 minuts, and then warmed to room temperature.After 1 hour, the reaction mixture was treated with a saturated solutionof ammonium chloride and extracted three times with ethyl acetate Theorganic phases were combined, washed with water and dried over Na2SO4.After removal of the solvent, the solid obtained was treated with etherand filtered to yield 0.67 g (40%) of a product whose structure wasconfirmed by ¹H-NMR. This compound was also prepared as is described inExample I-1a (Method c). The diastereomers were separated bycrystallization from acetonitrile and distinguished by ¹H-NMR.

EXAMPLE I-4d Preparation of 2-Hydroxy-2,2-difur-2-yl-acetic acid1-azabicyclo[2.2.2]oct-3(R)-yl ester

The title compound was synthesised as in example I-4c from intermediateI-4e- and 2-furanyl lithium which was prepared with furane and butyllithium following a standard method. The yield was 380 mg (8%). ¹H-NMR(CDCl3): δ 1.2-1.4 (m, 1H), 1.4-1.8 (m, 3H), 2.0 (m, 1H), 2.6-2.85 (m,5H), 3.2 (m, 1H), 5.0 (m, 1H), 6.4 (m, 3H), 7.3 (m, 1H), 7.5 (m, 2H). MS[M+1]⁺: 318.

EXAMPLE I-4e Preparation of oxofuran-2-yl-acetic acid1-azabicyclo[2.2.2]oct-3(R)-yl ester

Oxalyl chloride (9.75 ml, 0.112 mol) was added to a solution ofoxofuran-2-ylacetic acid (10 g, 0.071 mol) and dimethylformamide (onedrop) in 150 ml of chloroform (etanol free) at 01 C. The mixture wasstirred and allowed to warm at room temperature. After five hours thesolvent was evaporated. The residue was dissolved in chloroform andevaporated again. This procedure was repeated two times. The productobtained was disolved in CHCl3 (150 ml) and a solution of3(R)-quinuclidinol (10.90 g, 0.086 mol) in CHCl3 (150 ml) was added tothis at 01 C. The mixture was stirred and allowed to warm at roomtemperature. After 15 h at r.t., the mixture was washed with 10% aqueouspotassium carbonate, then with water, dried over Na2SO4 and evaporatedto give 9.34 g (52.5%) of the title compound as a dark oil. Structureconfirmed by NMR.

¹H-NMR (CDCl3): δ 1.40-1.60 (m, 1H), 1.60-1.80 (m, 2H), 1.80-2.05 (m,1H), 2.20 (m, 1H), 2.70-3.10 (m, 5H), 3.30-3.45 (m, 1H), 5.10 (m, 1H),6.7 (m, 1H), 7.7 (m, 1H), 7.8 (m, 1H).

EXAMPLE I-4f Preparation of 2-Hydroxy-2-phenyl-2-thien-2-ylacetic acid1-azabicyclo[2.2.2]oct-3(R)-yl ester

The title compound was prepared as described in example I-4c fromintermediate I-4g. The yield was 3 g (33%) as a mixture ofdiastereomers. After five crystallizations of 1.5 g of this mixture fromboiling isopropanol, 0.200 g of a pure diastereomer(1) were obtained.The mother liquors from first crystallization were enriched with theother diastereomer (2). Diastereomer 1 was hidrolysed to yield(+)-2-Hydroxy-2-phenyl-2-thien-2-ylacetic acid as a pure enantiomer,[α]²⁵ _(D)=+25.4 (c=2, EtOH). This value was assigned to the Rconfiguration provided that in literature (A. I. Meyers et.al. J. Org.Chem. (1980), 45(14), 2913) the 2(S) enantiomer has been described with[α]²⁵ _(D)=−20 (c=2, EtOH).

Diastereomer 1: 2(R)-2-Hydroxy-2-phenyl-2-thien-2-ylacetic acid 1-azabicyclo[2.2.2]oct-3(R)-yl ester. ¹H-NMR (DMSO-d6): δ 1.1-1.25 (m, 1H),1.3-1.6 (m, 3H), 1.83 (m, 1H), 2.4-2.7 (m, 5H), 3.1 (m, 1H), 4.8 (m,1H), 7.0 (m, 2H), 7.05 (m, 1H), 7.3-7.4 (m, 3H), 7.4-7.45 (m, 2H), 7.5(m, 1H).

Diastereomer 2: 2(S)-2-Hydroxy-2-phenyl-2-thien-2-ylacetic acid 1-azabicyclo[2.2.2]oct-3(R)-yl ester. ¹H-NMR (DMSO-d6): δ 1.1-1.25 (m, 1H),1.4-1.6 (m, 3H), 1.9 (m, 1H), 2.3-2.7 (m, 5H), 3.05 (m, 1H), 4.8 (m,1H), 7.0 (m, 2H), 7.05 (m, 1H), 7.3-7.4 (m, 3H), 7.4-7.45 (m, 2H), 7.5(m, 1H).

EXAMPLE I-4g Preparation of oxothien-2-yl-acetic acid1-azabicyclo[2.2.2]oct-3(R)-yl ester

Oxalyl chloride (1.34 ml, 0.0154 mol) was added to a solution ofoxothien-2-yl-acetic acid (2 g, 0.0128 mol) and dimethylformamide (onedrop) in 30 ml of chloroform (etanol free) at 01 C. The mixture wasstirred and allowed to warm at room temperature. After one hour thesolvent was evaporated. The residue was dissolved in chloroform andevaporated again. This procedure was repeated two times. The productobtained was disolved in CHCl3 (30 ml) and a solution of3(R)-quinuclidinol (1.95 g, 0.0154 mol) in CHCl3 (30 ml) was added tothis at 01 C. The mixture was stirred and allowed to warm at roomtemperature. After 1.5 h at r.t., the mixture was washed with 10%aqueous potassium carbonate, then with water, dried over Na2SO4 andevaporated to give 3.14 g (92.6%) of the title compound as a yellow oil.¹H-NMR (CDCl3): δ 1.40-1.50 (m, 1H), 1.50-1.70 (m, 1H), 1.70-1.80 (m,1H), 1.90-2.0 (m, 1H), 2.15 (m, 1H), 2.70-3.05 (m, 5H), 3.30-3.40 (m,1H), 5.05 (m, 1H), 7.20 (m, 1H), 7.85 (m, 1H), 8.10 (m, 1H).

Other carboxylic acids of Formula B—C(O)OH, whose preparation (or thesyntheses of their derivatives methyl ester, chloride or imidazolide)have not been described in methods c, d, e or in the Examples I-1e, I-1fand I-1g, and that are not commercially available, could be prepared asis described in the following references:

-   FR 2012964-   M. A. Davis et al; J. Med. Chem. (1963), 6, 513-516.-   T. Kumazawa et al; J. Med. Chem, (1994), 37(6), 804-810.-   M. A. Davis et al; J. Med. Chem., (1964), Vol (7), 88-94.-   Sestanj, K; Can. J. Chem., (1971), 49, 664-665.-   Burtner, R.; J. Am. Chem. Soc., (1943), 65, 1582-1585-   Heacock R. A. et al.; Ann. Appl. Biol., (1958), 46(3), 352-365.-   Rigaudy J. et. al.; Bull. Soc. Chim. France, (1959), 638-43.-   Ueda I. et al.; Bull. Chem. Soc. Jpn; (1975), 48 (8), 2306-2309.-   E. L. May et. al.; J. Am. Chem. Soc., (1948), 70, 1077-9.

Also included within the scope of the present invention arepharmaceutical composition which comprise, as the active ingredient, atleast one quinuclidine derivative of general formula (I) in associationwith a pharmaceutically acceptable carrier or diluent. Preferably thecomposition is made up in a form suitable for oral administration.

The pharmaceutically acceptable carrier or diluents which are mixed withthe active compound or compounds, to form the composition of thisinvention are well-known per se and the actual excipients used dependinter alia on the intended method of administration of the composition.

Compositions of this invention are preferably adapted for oraladministration. In this case, the composition for oral administrationmay take the form of tablets, film-coated tablets, liquid inhalant,powder inhalant and inhalation aerosol; all containing one or morecompounds of the invention; such preparations may be made by methodswell-known in the art.

The diluents which may be used in the preparations of the compositionsinclude those liquid and solid diluents which are compatible with theactive ingredient, together with colouring or flavouring agents, ifdesired. Tablets or film-coated tablets may conveniently contain between500 and 1 mg, preferably from 5 to 300 mg of active ingredient. Theinhalant compositions may contain between 1 Φg and 1,000 Φg, preferablyfrom 10 to 80 Φg of active ingredient. In human therapy, the dose of thecompound of general formula (I) depend on the desired effect andduration of treatment; adult doses are generally between 3 mg and 300 mgper day as tablets and 10 Φg and 800 Φg per day as inhalant composition.

Pharmacological Action

The following examples demonstrate the excellent pharmacologicalactivities of the compounds of the present invention. The results onhuman muscarinic receptors binding and in the test on bronchospasm inguinea pig, were obtained as described below.

Human Muscarinic Receptor Studies.

The binding of [³H]-NMS to human muscarinic receptors was performedaccording to Waelbroek et al (1990) (1). Assays were carried out at 25°C. Membrane preparations from stably transfected chinese hamsterovary-K1 cells (CHO) expressing the genes for the human muscarinicreceptors Hm3 were used.

For determination of IC₅₀, membrane preparations were suspended in DPBSto a final concentration of 89 μg/ml for the Hm3 subtype. The membranesuspension was incubated with the tritiated compound for 60 min. Afterincubation the membrane fraction was separated by filtration and thebound radioactivity determined. Non specific binding was determined byaddition of 10⁻⁴ M atropine. At least six concentrations were assayed induplicate to generate individual displacement curves.

COMPOUNDS BINDING TO RECEPTOR No M₃ (IC₅₀ nM) ATROPINE 3.2 IPRATROPIUM3.0 1 31 2 15 7 22 8 4.8 17 14 18 6.6 20 6.8 35 13 36 2.7 39 3.8 44 4.453 5.6 71 8.2 74 16 77 3.1 78 5 84 9.9 89 5.4 99 31 100 14 101 7.6 10931 114 14 116 23 126 13 127 16 128 8.8 129 6.3 136 11 137 6.9 138 19 14613(1) M. Waelbroek M. Tastenoy, J. Camus, J Christophe. Binding ofselective antagonists to four muscarinic receptors (M1 to M4) in ratforebrain Mol. Pharmacol. (1990) 38: 267-273.

Our results show that the compounds of the present invention haveaffinities for the M₃ receptors which are very similar to the referencecompounds.

The compounds of the invention preferably have high affinities formuscarinic M₃ receptors (HM3), preferably human muscarinic receptors.Affinity levels can typically be measured by in vitro assays, forexample, as described above.

Preferred compounds of the invention have an IC₅₀ (nM) value for M₃receptors of less than 35, preferably less than 25, 20 or 15, morepreferably less than 10, 8 or 5.

Test on Bronchospasm in Guinea Pig

The studies were performed according to Konzett and Rössler (2). Aqueoussolutions of the agents to be tested were nebulized and inhaled byanaesthetized ventilated male guinea pigs (Dunkin-Hartley). Thebronchial response to intravenous acetylcholine challenge was determinedbefore and after drug administration and the percent change in pulmonaryresistance at several time-points.

2. Konzett H., Rössler F. Versuchsanordnung zu Untersuchungen anderbronchialmuskulatur. Arch. Exp. Path. Pharmacol. 195: 71-74 (1940)

The compounds of the present invention inhibited the bronchospasmresponse to acetylcholine with high potency and a long duration ofaction.

From the above described results one of ordinary skill in the art canreadily understand that the compounds of the present invention haveexcellent antimuscarinic activity (M₃) and thus are useful for thetreatment of diseases in which the muscarinic M₃ receptor is implicated,including respiratory diseases such as chronic obstructive pulmonarydisease, chronic bronchitis, asthma and rhinitis, urinary diseases suchas urinary incontinence and pollakinuria in neuripenia pollakinuria,neurogenic bladder, nocturnal enuresis, unstable bladder, cystospasm andchronic cystitis and gastrointestinal diseases such as irritable bowelsyndrome, spastic colitis and diverticulitis.

The present invention further provides a compound of formula (I) or apharmaceutically acceptable composition comprising a compound of formula(I) for use in a method of treatment of the human or animal body bytherapy, in particular for the treatment of respiratory, urinary orgastrointestinal disease.

The present invention further provides the use of a compound of formula(I) or a pharmaceutically acceptable composition comprising a compoundof formula (I) for the manufacture of a medicament for the treatment ofrespiratory, urinary or gastrointestinal disease.

Further, the compounds of formula (I) and pharmaceutical compositionscomprising a compound of formula (I) can be used in a method of treatingrespiratory, urinary or gastrointestinal disease, which method comprisesadministering to a human or animal patient in need of such treatment aneffective amount of a compound of formula (I) or a pharmaceuticalcomposition comprising a compound of formula (I).

The present invention will be further illustrated by the followingexamples. The examples are given by way of illustration only and are notto be construed as limiting.

EXAMPLE 13(R)-Diphenylacetoxy-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods d and a. Theyield of final step was 500 mg, 81%. ¹H-NMR (CDCl₃): δ 1.72-2.18 (m,6H), 2.35 (m, 1H), 3.0 (m, 1H), 3.23 (m, 1H), 3.59-3.88 (m, 5H), 4.0 (m,2H), 4.30 (m, 1H), 5.1 (s, 1H), 5.25 (m, 1H), 6.8-6.9 (m, 2H), 6.9-7.0(m, 1H), 7.2-7.4 (m, 12H); MS [M-Br]⁺: 456; mp 129° C.

EXAMPLE 23(R)-(2-Hydroxy-2,2-diphenylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 280 mg, 42%. ¹H-NMR (DMSO-d6): δ 1.5-1.7 (m,2H), 1.9-2.1 (m, 4H), 2.3 (m, 1H), 3.1 (m, 1H), 3.2-3.5 (m, 6H), 3.9-4.1(m, 3H), 5.25 (m, 1H), 6.8 (bs, OH), 6.95 (m, 3H), 7.2-7.5 (m, 12H); MS[M-Br]⁺: 472; mp 199° C.

EXAMPLE 33(R)-[2,2-Bis(4-fluorophenyl)-2-hydroxyacetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 400 mg, 85%. ¹H-NMR (DMSO-d6): δ 1.5-1.65 (m,1H), 1.7-1.8 (m, 1H), 1.85-2.0 (m, 2H), 2.05-2.2 (m, 2H), 2.3 (m, 1H),3.1-3.2 (m, 1H), 3.3-3.5 (m, 6H), 3.95 (m, 1H), 4.05 (m, 2H), 5.25 (m,1H), 6.9-7.0 (m, 4H), 7.1-7.5 (m, 10H); MS [M-Br]⁺: 508; mp 253° C.

EXAMPLE 43(R)-[2,2-Bis(4-fluorophenyl)-2-hydroxyacetoxy]-1-phenethyl-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 300 mg, 67%. ¹H-NMR (DMSO-d6): δ 1.5-1.65 (m,1H), 1.7-1.85 (m, 1H), 1.85-2.1 (m, 2H), 2.3 (m, 1H), 2.9-3.1 (m, 2H),3.15-3.25 (m, 1H), 3.3-3.6 (m, 6H), 3.95-4.05 (m, 1H), 5.25 (m, 1H),6.95 (s, OH), 7.1-7.5 (m, 13H); MS [M-Br]⁺: 478; mp 182° C.

EXAMPLE 53(R)-(2-Hydroxy-2,2-di-p-tolylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 500 mg, 54%. ¹H-NMR (DMSO-d6): δ 1.55-1.8 (m,2H), 1.85-2.0 (m, 2H), 2.05-1.15 (m, 2H), 2.3 (s, 7H), 3.05-3.15 (m,1H), 3.25-3.5 (m, 6H), 3.95 (m, 1H), 4.05 (t, 2H), 5.2 (m, 1H), 6.8 (s,OH), 6.95 (m, 3H), 7.1-7.2 (m, 4H), 7.2-7.35 (m, 6H); MS [M-Br]⁺:500; mp183° C.

EXAMPLE 63(R)-(2-Hydroxy-2,2-di-p-tolylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 650 mg, 74%. ¹H-NMR (DMSO-d6): δ 1.55-1.8 (m,2H), 1.85-2.05 (m, 2H), 2.25 (s, 7H), 2.9-3.05 (m, 2H), 3.1-3.25 (m,1H), 3.3-3.55 (m, 6H), 3.95 (m, 1H), 5.25 (m, 1H), 6.8 (s, OH), 7.1-7.2(m, 4H), 7.2-7.35 (m, 9H); MS [M-Br]⁺:470; mp 144° C.

EXAMPLE 73(R)-(2,2-Diphenylpropionyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods e and a. Theyield of final step was 250 mg, 61%. ¹H-NMR (CDCl₃): δ 1.47-1.60 (m,1H), 1.8-2.0 (m, 1H), 2.0 (s, 3H), 2.0-2.15 (m, 4H), 2.39 (s, 1H), 2.6(m, 1H), 2.92 (d, 1H), 3.6 (m, 1H), 3.7-3.9 (m, 4H), 4.0 (m, 2H), 4.3(m, 1H), 5.25 (m, 1H), 6.85 (m, 2H), 7.0 (m, 1H), 7.3 (m, 12H); MS[M-Br]⁺: 470; mp 186° C.

EXAMPLE 83(R)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised as a mixture of diastereomersaccording to methods c and a. The yield of final step was 520 mg, 62%.¹H-NMR (DMSO-d6): δ 1.5-1.95 (m, 4H), 2.1 (m, 2H), 2.3 (m, 1H), 3.1 (m,1H), 3.3-3.5 (m, 6H), 3.9 (m, 1H), 4.05 (t, 2H), 5.2 (m, 1H), 7.0 (m,4H), 7.15 (m, 2H), 7.35 (m, 5H), 7.5 (m, 3H); MS [M-Br]⁺: 478; mp 220°C.

EXAMPLE 93(R)-[2(R)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy)]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods f and b fromintermediate I-4f, diastereomer 1. The yield of final step was 10 mg,23%. ¹H-NMR (DMSO-d6): δ 1.5-1.6 (m, 1H), 1.65-1.75 (m, 1H), 1.8-2.0 (m,2H), 2.05-2.1 (m, 2H), 2.3 (m, 1H), 3.05-3.2 (m, 1H), 3.25-3.55 (m, 6H),3.85-3.95 (m, 1H), 4.0 (t, 2H), 5.2 (m, 1H), 6.95 (m, 3H), 7.03 (m, 1H),7.15 (dd, 1H), 7.2 (s, OH), 7.3-7.5 (m, 5H), 7.45-7.55 (m, 3H); MS[M-CF3COO]⁺: 478.

EXAMPLE 103(R)-[2(S)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy)]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane; trifluoroacetate

The title compound was synthesised according to methods f and b fromintermediate I-4f, diastereomer 2. The yield of final step was 3 mg,11%. ¹H-NMR (DMSO-d6): δ 1.6-1.75 (m, 2H), 1.8-2.0 (m, 4H), 2.25 (m,1H), 2.8 (t, 2H), 2.95-3.1 (m, 1H), 3.15-3.5 (m, 6H), 3.8-3.95 (m, 1H),5.2 (m, 1H), 6.92 (m, 1H), 6.96-7.03 (m, 2H), 7.1 (dd, 1H), 7.18 (s,OH), 7.3-7.4 (m, 4H), 7.43-7.5 (m, 2H), 7.51 (dd, 1H); MS [M-CF3COO]⁺:478.

EXAMPLE 113(R)-[2(R)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy)]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods f and b fromintermediate I-4f, diastereomer 1. The yield of final step was 9 mg,22%. ¹H-NMR (DMSO-d6): δ 1.45-1.55 (m, 1H), 1.65-1.75 (m, 1H), 1.85-2.05(m, 2H), 2.3 (m, 1H), 2.9-3.1 (m, 2H), 3.1-3.25 (m, 1H), 3.25-3.55 (m,6H), 3.9-4.0 (m, 1H), 5.25 (m, 1H), 7.05 (m, 1H), 7.15 (m, 1H), 7.2 (m,1H), 7.25-7.4 (m, 8H), 7.45 (m, 2H, 7.55 (m, 1H); MS [M-CF3COO]⁺: 448.

EXAMPLE 123(R)-[2(R)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy)]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods f and b fromintermediate I-4f, diastereomer 1. The yield of final step was 11 mg,26%. ¹H-NMR (DMSO-d6): δ 1.45-1.55 (m, 1H), 1.6-1.75 (m, 1H), 1.8-2.0(m, 4H), 2.25 (m, 1H), 2.55 (t, 2H), 3.0-3.1 (m, 1H), 3.15-3.55 (m, 6H),3.8-3.9 (m, 1H), 5.2 (m, 1H), 7.0 (m, 1H), 7.1 (m, 1H), 7.15-7.4 (m,9H), 7.45 (m, 2H), 7.5 (m, 1H); MS [M-CF3COO]⁺: 462.

EXAMPLE 133(R)-[2(R)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy)]-1-(2-thien-2-ylethyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods f and b fromintermediate I-4f, diastereomer 1. The yield of final step was 10 mg,24%. ¹H-NMR (DMSO-d6): δ 1.45-1.55 (m, 1H), 1.65-1.75 (m, 1H), 1.8-2.0(m, 2H), 2.3 (m, 1H), 3.1-3.6 (m, 9H), 3.9-4.0 (m, 1H), 5.25 (m, 1H),7.0 (m, 3H), 7.15 (dd, 1H), 7.2 (s, OH), 7.3-7.4 (m, 3H), 7.45-7.55 (m,4H); MS [M-CF3COO]⁺:454.

EXAMPLE 143(R)-[2(R)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy)]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods f and b fromintermediate I-4f, diastereomer 1. The yield of final step was 8 mg,19%. ¹H-NMR (DMSO-d6): δ 1.45-1.6 (m, 1H), 1.65-1.75 (m, 1H), 1.8-2.05(m, 4H), 2.25 (m, 1H), 2.8 (t, 2H), 3.0-3.15 (m, 1H), 3.2-3.5 (m, 6H),3.8-3.95 (m, 1H), 5.2 (m, 1H), 6.92 (m, 1H), 6.96-7.03 (m,2H), 7.13 (dd,1H), 7.2 (s, OH), 7.3-7.4 (m, 4H), 7.45-7.5 (m, 2H), 7.52 (dd, 1H); MS[M-CF3COO]⁺: 468.

EXAMPLE 153(R)-[2(S)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy)]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods f and b fromintermediate I-4f, diastereomer 2. The yield of final step was 7 mg,26%. ¹H-NMR (DMSO-d6): δ 1.6-1.75 (m, 2H), 1.8-2.0 (m, 4H), 2.25 (m,1H), 2.8 (t, 2H), 2.95-3.1 (m, 1H), 3.15-3.5 (m, 6H), 3.8-3.95 (m, 1H),5.2 (m, 1H), 6.92 (m, 1H), 6.96-7.03 (m, 2H), 7.1 (dd, 1H), 7.18 (s,OH), 7.3-7.4 (m, 4H), 7.43-7.5 (m, 2H), 7.51 (dd, 1H); MS [M-CF3COO]⁺:468.

EXAMPLE 163(R)-[2(R)-(2-Hydroxy-2-phenyl-2-thien-2-ylacetoxy)]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods f and b fromintermediate I-4f, diastereomer 1. The yield of final step was 11 mg,26%. ¹H-NMR (DMSO-d6): δ 1.5-1.6 (m, 1H), 1.65-1.75 (m, 1H), 1.8-2.0 (m,2H), 2.25 (m, 1H), 3.15-3.6 (m, 5H), 3.7 (m, 2H), 4.0 (m, 2H), 4.4 (m,2H), 5.25 (m, 1H), 6.95-7.03 (m, 4H), 7.12 (dd, 1H), 7.2 (s, OH),7.3-7.4 (m, 5H), 7.4-7.5 (m, 3H); MS [M-CF3COO]⁺: 464.

EXAMPLE 173(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2.2]octane;bromide

The title compound was synthesised as a mixture of diastereomersaccording to methods c and a. The yield of final step was 240 mg, 77%.¹H-NMR (DMSO-d6): δ 1.55-2.0 (m, 4H), 2.27 (m, 1H), 3.05-3.55 (m, 5H),3.88-3.98 (m, 1H), 4.0-4.10 (m, 2H), 5.21 (m, 1H), 6.23-6.31 (double dd,1H), 6.36-6.48 (m, 2H), 6.83-6.90 (dd, 1H), 6.95 (d, OH), 7.26-7.66 (m,11H); MS [M-Br]⁺: 444; mp 99° C.

EXAMPLE 183(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised as a mixture of diastereomersaccording to methods c and a. The yield of final step was 210 mg, 66%.¹H-NMR (DMSO-d6): δ 1.50-2.05 (m, 4H), 2.27 (m, 1H), 3.20 (m, 1H),3.37-3.65 (m, 4H), 3.65-3.75 (m, 2H), 4.04 (m, 1H), 4.40 (m, 2H), 5.21(m, 1H), 6.23-6.32 (double dd, 1H), 6.44 (m, 1H), 6.94-7.04 (m, 4H),7.33-7.50 (m, 7H), 7.64 (m, 1H); MS [M-Br]⁺: 448; mp 163° C.

EXAMPLE 193(R)-[2(*)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b fromintermediate I-1a, diastereomer 1. The yield of final step was 11 mg,23%. ¹H-NMR (DMSO-d6): δ 1.65-1.80 (m, 2H), 1.80-2.10 (m, 2H), 2.27 (m,1H), 3.15-3.65 (m, 5H), 3.68 (m, 2H), 4.0 (m, 1H), 4.40 (t, 2H), 5.20(m, 1H), 6.23 (d, 1H), 6.42 (m, 1H), 6.92-7.04 (m, 4H), 7.30-7.38 (m,5H), 7.44-7.50 (m, 2H), 7.64 (m, 1H); MS [M-CF3COO]⁺: 448.

EXAMPLE 203(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound has been described in method -a-.

EXAMPLE 213(R)-[2(*)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods c and a fromintermediate I-1a, diastereomer 1. The yield of final step was 1.15 g99%. ¹H-NMR (DMSO-d6): δ 1.60-2.20 (m, 6H), 2.25 (m, 1H), 3.10 (m, 1H),3.20-3.60 (m, 6H), 3.95 (m, 1H), 4.05 (m, 2H), 5.20 (m, 1H), 6.25 (dd,1H), 6.45 (m, 1H), 6.95 (m, 4H), 7.30-7.50 (m, 7H), 7.70 (m, 1H); MS[M-Br]⁺: 462; mp156° C.

EXAMPLE 223(R)-[2(*)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised-according to methods c and b fromintermediate I-1a, diastereomer 2. The yield of final step was 10 mg,20%. ¹H-NMR (DMSO-d6): δ 1.50-2.20 (m, 6H), 2.25 (m, 1H), 3.10 (m, 1H),3.20-3.60 (m, 6H), 3.95 (m, 1H), 4.05 (m, 2H), 5.20 (m, 1H), 6.35 (dd,1H), 6.45 (m, 1H), 6.95 (m, 4H), 7.30-7.50 (m, 7H), 7.70 (m, 1H); MS[M-CF3COO]⁺: 462.

EXAMPLE 233(R)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised as a mixture of diastereomersaccording to methods c and b. The yield of final step was 12 mg, 13%.¹H-NMR (DMSO-d6): δ 1.5 (m, 1H), 1.7 (m, 1H), 1.9-2.05 (m, 2H), 2.3 (m,1H), 2.95 (m, 2H), 3.15 (m, 1H), 3.25-3.55 (m, 6H), 3.95 (m, 1H), 5.25(m, 1H), 6.3 (d, 1H), 6.45 (m, 1H), 6.95 (d, 1H), 7.25-7.45 (m, 8H), 7.5(m, 2H), 7.7 (m, 1H); MS [M-CF₃COO]⁺: 432.

EXAMPLE 243(R)-[2(*)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)]-1-phenethyl-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b fromintermediate I-1a, diastereomer 1. The yield of final step was 16 mg,40%. ¹H-NMR (DMSO-d6): δ 1.65-1.80 (m, 2H), 1.90-2.05 (m, 2H), 2.3 (m,1H), 2.95 (m, 2H), 3.15 (m, 1H), 3.25-3.55 (m, 6H), 3.95 (m, 1H), 5.25(m, 1H), 6.26 (dd, 1H), 6.46 (m, 1H), 6.95 (s, 1H, OH), 7.25-7.45 (m,8H), 7.5 (m, 2H), 7.7 (m, 1H); MS [M-CF3COO]⁺: 432.

EXAMPLE 253(R)-[2(*)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)]-1-phenethyl-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised-according to methods c and b fromintermediate I-1a, diastereomer 2. The yield of final step was 14 mg,35%. ¹H-NMR (DMSO-d6): δ 1.50-1.80 (m, 2H), 1.90-2.05 (m, 2H), 2.3 (m,1H), 2.95 (m, 2H), 3.15 (m, 1H), 3.25-3.55 (m, 6H), 3.95 (m, 1H), 5.25(m, 1H), 6.32 (dd, 1H), 6.46 (m, 1H), 6.95 (s, 1H, OH), 7.25-7.45 (m,8H), 7.5 (m, 2H), 7.7 (m, 1H); MS [M-CF3COO]⁺: 432.

EXAMPLE 263(R)-[2(*)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b fromintermediate I-1a, diastereomer 1. The yield of final step-was 10 mg,21%. ¹H-NMR (DMSO-d6): δ 1.60-1.75 (m, 2H), 1.80-2.0 (m, 4H), 2.25 (m,1H), 2.50-2.60 (m, 2H), 3.0 (m, 1H), 3.10-3.50 (m, 6H), 3.83 (m, 1H),5.17 (m, 1H), 6.25 (d, 1H), 6.45 (m, 1H), 6.95 (s, 1H), 7.20-7.40 (m,8H), 7.46-7.48 (m, 2H), 7.66 (m, 1H); MS [M-CF3COO]⁺: 446.

EXAMPLE 273(R)-[2(*)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)]-1-(2-thien-2-ylethyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b fromintermediate I-1a, diastereomer 1. The yield of final step was 9 mg,19%. ¹H-NMR (DMSO-d6): δ 1.65-1.80 (m, 2H), 1.85-2.05 (m, 2H), 2.30 (m,1H), 3.10-3.40 (m, 3H), 3.40-3.60 (m, 6H), 3.95 (m, 1H), 5.24 (m, 1H),6.27 (d, 1H), 6.47 (m, 1H), 6.96 (s, 1H), 7.0-7.04 (m 2H), 7.36-7.48 (m,4H), 7.49-7.54 (m, 2H), 7.70 (m, 1H).; MS [M-CF3COO]⁺: 438.

EXAMPLE 283(R)-[2(*)-(2-Furan-2-yl-2-hydroxy-2-phenylacetoxy)]-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b fromintermediate I-1a, diastereomer 1. The yield of final step was 9 mg,19%. ¹H-NMR (DMSO-d6): δ 1.60-1.75 (m, 2H), 1.80-2.05 (m, 4H), 2.26 (m,1H), 2.81 (t, 2H), 3.02 (m, 1H), 3.10-3.45 (m, 6H), 3.85 (m, 1H), 5.18(m, 1H), 6.25 (d, 1H), 6.45 (m, 1H), 6.90-7.0 (m, 3H), 7.32-7.42 (m,4H), 7.45-7.51 (m, 2H), 7.66 (m, 1H); MS [M-CF3COO]⁺: 452.

EXAMPLE 293(R)-(2-Furan-2-yl-2-hydroxy-2-thien-2-ylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised as a mixture of diastereomersaccording to methods c and b. The yield of final step was 18 mg, 20%.¹H-NMR (DMSO-d6): δ 1.65-2.05 (m, 4H), 2.3 (m, 1H), 3.0 (m, 2H),3.15-3.6 (m, 7H), 3.95 (m, 1H), 5.25 (m, 1H), 6.35 (dd, 1H), 6.45 (m,1H), 7.05 (m, 1H), 7.2 (dd, 1H), 7.25-7.5 (m, 6H), 7.55 (m, 1H), 7.65(m, 1H); MS [M-CF₃COO]⁺: 438.

EXAMPLE 303(R)-(2-Furan-2-yl-2-hydroxy-2-thien-2-ylacetoxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised as a mixture of diastereomersaccording to methods c and b. The yield of final step was 22 mg, 23%.¹H-NMR (DMSO-d6): δ 2.65-2.05 (m, 4H), 2.3 (m, 1H), 3.15-3.65 (m, 7H),4.05 (m, 1H), 4.4 (m, 2H), 5.15 (m, 1H), 6.35 (dd, 1H), 6.45 (m, 1H),6.95-7.05 (m, 4H), 7.15 (d, 1H), 7.3-7.4 (m, 3H), 7.5 (dd, 1H), 7.65 (d,1H); MS [M-CF₃COO]⁺: 454.

EXAMPLE 313(R)-(2-Furan-2-yl-2-hydroxy-2-thien-2-ylacetoxy)-1-(4-oxo-4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised as a mixture of diastereomersaccording to methods c and b. The yield of final step was 15.4 mg, 15%.¹H-NMR (DMSO-d6): δ 1.65-2.1 (m, 6H), 7.05-7.55 (m, 9H), 3.95 (m, 1H),5.1 (m, 1H), 6.35 (dd, 1H), 6.5 (m, 1H), 7.05 (m, 1H), 7.15 (m, 1H), 7.3(d, 1H), 7.55 (m, 3H), 7.7 (dd, 2H), 8.0 (d, 2H); MS [M-CF₃COO]⁺: 480.

EXAMPLE 321-(3-phenoxypropyl)-3(R)-(2-Furan-2-yl-2-hydroxy-2-thien-2-yl-acetoxy)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised as a mixture of diastereomersaccording to methods c and a. The-yield of final step was 100 mg, 41%.¹H-NMR (DMSO-d6): δ 1.65-2.05 (m, 4H), 2.1-2.0 (m, 2H), 2.3 (m, 1H),3.15 (m, 1H), 3.25-3.6 (6H), 3.9-4.1 (m, 3H), 5.1 (m, 1H), 6.35 (d, 1H),6.45 (s, 1H), 6.95 (m, 3H), 7.05 (m, 1H), 7.2 (d, 1H), 7.3 (m, 3H), 7.55(d, 1H), 7.7 (s, 1H); MS [M-Br]⁺: 520; mp 173° C.

EXAMPLE 331-(3-phenoxypropyl)-3(R)-(2,2-difuran-2-yl-2-hydroxyacetoxy)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods f and a. Theyield of final step was 200 mg, 60%. ¹H-NMR (DMSO-d6): δ 1.6-2.20 (m,6H), 2.3 (m, 1H), 2.95-3.65 (m, 7H), 3.80-4.10 (m, 3H), 5.2 (m, 1H),6.3-6.6 (m, 4H), 6.8-7.0 (m, 3H), 7.1 (s, OH), 7.3 (m, 2H), 7.7 (m, 2H);MS [M-Br]⁺: 452.

EXAMPLE 343(R)-(2,2-Dithien-2-ylacetoxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 240 mg, 60%. ¹H-NMR (DMSO-d6): δ 1.85-2.10 (m,4H), 2.30 (s, 1H), 3.40 (m, 1H), 3.44-3.80 (m, 6H), 4.10 (m, 1H), 4.45(m, 2H), 5.20 (m, 1H), 5.90 (s, 1H), 6.95-7.05 (m, 5H), 7.05-7.15 (m,2H), 7.30-7.40 (m, 2H), 7.45 (m, 2H); MS [M-Br]⁺: 454; mp 98° C.

EXAMPLE 353(R)-(2,2-Dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 280 mg, 83%. ¹H-NMR (DMSO-d6): δ 1.80-2.06 (m,4H), 2.06-2.20 (m, 2H), 2.20-2.30 (m, 1H), 3.20-3.65 (m, 7H), 3.90-4.10(m, 3H), 5.20 (m, 1H), 5.90 (s, 1H), 6.95-7.05 (m, 5H), 7.05-7.20 (m,2H), 7.30-7.35 (m, 2H), 7.50 (m, 2H); MS [M-Br]⁺: 468; mp 148° C.

EXAMPLE 363(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 180 mg, 59%. ¹H-NMR (DMSO-d6): δ 1.65-2.0 (4H,m), 2.35 (m, 1H), 3.0 (m, 2H), 3.2-3.6 (m, 7H), 3.95 (m, 1H), 5.25 (m,1H), 7.0 (m, 2H), 7.2 (m, 2H), 7.35 (m, 5H), 7.55 (m, 3H); MS [M-Br]⁺:454; mp 216° C.

EXAMPLE 373(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 450 mg, 58%. ¹H-NMR (CDCl₃): δ 1.8-2.1 (m, 6H),2.4 (m, 1H), 2.6 (m, 2H), 3.4-3.8 (m, 7H), 4.2 (m, 1H), 5.25 (m, 1H),6.1 (bs, OH), 6.9 (m, 2H), 7.1-7.3 (m, 9H); MS [M-Br]⁺: 468; mp 64° C.

EXAMPLE 383(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 260 mg, 34%. ¹H-NMR (CDCl₃): δ 1.8-2.05 (m, 4H),2.4 (m, 1H), 3.55-3.95 (m, 5H), 4.15-4.5 (m, 3H), 5.25 (m, 1H), 5.9 (s,OH), 6.15 (m, 1H), 6.85 (t, 1H), 6.9-7.05 (m, 3H), 7.15 (m, 1H),7.2-7.45 (m, 7H); MS [M-Br]⁺: 466; mp 124° C.

EXAMPLE 393(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 320 mg, 40%. ¹H-NMR (CDCl₃): δ 1.6-2.0 (m, 8H),2.4 (m, 1H), 2.6 (m, 2H), 3.4-3.8 (m, 7H), 4.2 (m, 1H), 5.25 (m, 1H),6.05 (bs, OH), 6.95 (m, 2H), 7.1-7.3 (m, 9H); MS [M-Br]⁺: 482; mp 64° C.

EXAMPLE 403(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(4-oxo-4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 16 mg, 15%. ¹H-NMR (DMSO-d6): δ 1.7-2.0 (m, 6H),2.15 (m, 1H), 3.1 (t, 2H), 3.15-3.55 (m, 7H), 3.95 (m, 1H), 5.25 (m,1H), 7.0 (d, 2H), 7.15 (d, 2H), 7.55 (m, 5H), 7.65 (t, 1H), 8.0 (d, 2H);MS[M-CF₃COO]⁺: 496.

EXAMPLE 413(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenylaminopropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 14 mg, 14%. ¹H-NMR (DMSO-d6): δ 1.7-2.0 (m, 5H),2.3 (m, 1H), 3.0-3.5 (m, 9H), 3.9 (m, 1H), 5.25 (m, 1H), 5.65 (t, 1H),6.55 (m, 3H), 7.0 (d, 2H), 7.1 (t, 2H), 7.15 (m, 2H), 7.5 (m, 3H);MS[M-CF₃COO]⁺: 483.

EXAMPLE 423(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(methylphenylamino)propyl]-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 20 mg, 19%. ¹H-NMR (DMSO-d6): δ 1.65-2.0 (m,6H), 2.9 (s, 3H), 3.1 (m, 1H), 3.2-3.45 (m, 8H), 3.95 (m, 1H), 5.2 (m,1H), 6.65 (t, 1H), 6.75 (d, 2H), 7.0 (m, 2H), 7.2 (m, 4H), 7.5 (m, 3H);MS [M-CF₃COO]⁺: 497.

EXAMPLE 433(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenylsulfanylpropyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 800 mg, 83%. ¹H-NMR (DMSO-d6): δ 1.6-1.9 (m,6H), 2.3 (m, 1H), 2.95 (t, 2H), 3.05 (m, 1H), 3.2-3.5 (m, 6H), 3.9 (m,1H), 5.2 (m, 1H), 7.0 (m, 2H), 7.15 (m, 2H), 7.2 (m, 1H), 7.35 (m, 4H),7.5 (m, 2H); MS [M-Br]⁺: 500.

EXAMPLE 443(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 490 mg, 90%. ¹H-NMR (DMSO-d6): δ 1.7 (m, 2H),1.95 (m, 2H), 2.1 (m, 2H), 2.3 (m, 1H), 3.2 (m, 1H), 3.45 (m, 6H), 4.0(m, 3H), 5.15 (m, 1H), 6.9 (m, 3H), 7.0 (m, 2H), 7.2 (m, 2H), 7.3 (t,2H), 7.5 (m, 3H); MS [M-Br]⁺: 484; mp 227° C.

EXAMPLE 453(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-o-tolyloxypropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b Theyield of final step was 19 mg, 18%. ¹H-NMR (DMSO-d6): δ 1.7-2.0 (m, 4H),2.1-2.2 (m, 5H), 2.3 (m, 1H), 3.15-3.5 (m, 7H), 3.9-4.05 (m, 3H), 5.05(m, 1H), 6.85 (t, 1H), 6.9 (d, 1H), 7.0 (m, 2H), 7.15 (m, 4H), 7.5 (m,3H); MS [M-CF₃COO]⁺: 498.

EXAMPLE 463-(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(2,4,6-trimethylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 22 mg, 20%. ¹H-NMR (DMSO-d6): δ 1.7 (m, 2H),1.95 (m, 2H), 2.1 (m, 2H), 2.2 (s, 9H), 2.35 (m, 1H), 3.2-3.5 (m, 7H),3.7 (t, 2H), 3.95 (m, 1H), 5.25 (m, 1H), 6.8 (s, 2H), 7.0 (m, 2H), 7.2(m, 2H), 7.5 (m, 3H); MS [M-CF₃COO]⁺: 526.

EXAMPLE 471-[3-(2-tert-Butyl-6-methylphenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 18 mg, 16%. ¹H-NMR (DMSO-d6): δ 1.3 (s, 9H), 2.7(m, 2H), 2.9 (m, 2H), 2.1 (m, 2H), 2.2 (s, 3H), 2.3 (m, 1H), 3.2-3.5 (m,7H), 3.8 (t, 2H), 3.95 (m, 1H), 5.2 (m, 1H), 6.9-7.15 (m, 7H), 7.5 (m,3H); MS [M-CF₃COO]⁺: 554.

EXAMPLE 481-[3-(Biphenyl-4-yloxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]-octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 22 mg, 19%. ¹H-NMR (DMSO-d6): δ 1.7 (m, 2H), 1.9(m, 2H), 2.15 (m, 2H), 2.3 (m, 1H), 3.2-3.5 (m, 7H), 3.95 (m, 1H), 4.1(t, 2H), 5.25 (m, 1H), 7.0 (m, 4H), 7.2 (m, 2H), 7.3 (t, 1H), 7.45 (t,2H), 7.5 (m, 3H), 7.6 (m, 4H); MS [M-CF₃COO]⁺: 560.

EXAMPLE 493(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(5,6,7,8-tetrahydronaphthalen-2-yloxy)-propyl]-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 23 mg, 21%. ¹H-NMR (DMSO-d6): δ 1.7 (m, 6H),1.9-2.1 (m, 4H), 2.3 (m, 1H), 2.65 (m, 4H), 3.15-3.5 (m, 7H), 3.95 (m,2H), 5.25 (m, 1H), 6.65 (m, 2H), 6.95 (d, 1H), 7.0 (m, 2H), 7.2 (m, 2H),7.5 (m, 3H); MS [M-CF₃COO]⁺: 538.

EXAMPLE 503(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(naphthalen-2-yloxy)propyl]-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 17 mg, 15%. ¹H-NMR (DMSO-d6): δ 1.7-2.0 (m, 4H),2.1 (m, 1H), 2.35 (m, 1H), 3.15-3.35 (m, 7H), 3.95 (m, 1H), 4.17 (t,2H), 5.25 (m, 1H), 7.0 (m, 2H), 7.15 (m, 3H), 7.35 (m, 2H), 7.5 (m, 4H),7.85 (m, 3H); MS [M-CF₃COO]⁺: 534.

EXAMPLE 513(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(naphthalen-1-yloxy)propyl]-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound has been described in method -b-.

EXAMPLE 521-[3-(2-Chlorophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 20 mg, 18%. ¹H-NMR (DMSO-d6): δ 1.65-2.0 (m,6H), 2.35 (m, 1H), 3.2 (m, 1H), 3.3-3.55 (m, 6H), 3.95 (m, 1H), 4.15 (t,2H), 5.25 (m, 2H), 7.0 (m, 3H), 7.2 (m, 3H), 7.35 (t, 1H), 7.45 (d, 1H),7.55 (m, 3H); MS [M-CF₃COO]⁺: 519.

EXAMPLE 531-[3-(4-Fluorophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane;chloride

The title compound was synthesised according to methods c and a. Theyield of final step was 180 mg, 59%. ¹H-NMR (DMSO-d6): δ 1.65-2.15 (m,6H), 2.25 (m, 1H), 3.2 (m, 1H), 3.25-3.55 (m, 6H), 3.95 (m, 2H), 4.0 (t,2H), 5.25 (m, 1H), 7.0 (m, 4H), 7.15 (m, 4H), 7.55 (m, 3H); MS [M-Cl]⁺:502; mp 160° C.

EXAMPLE 541-[3-(2,4-Difluorophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 14 mg, 13%. ¹H-NMR (DMSO-d6): δ 1.65-2.0 (m,4H), 2.15 (m, 2H), 2.35 (m, 1H), 3.2 (m, 1H), 3.25-3.35 (m, 6H), 3.95(m, 1H), 4.1 (t, 2H), 5.15 (m, 1H), 7.05 (m, 3H), 7.2 (d, 2H), 7.25-7.35(m, 2H), 7.55 (m, 3H); MS [M-CF₃COO]+: 520.

EXAMPLE 553(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(3-trifluoromethylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane; trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 19 mg, 17%. ¹H-NMR (DMSO-d6): δ 1.65-2.1 (m,6H), 2.35 (m, 1H), 3.2 (m, 1H), 3.3-3.55 (m, 6H), 3.95 (m, 1H), 4.15 (t,2H), 5.25 (m, 1H), 7.0 (m, 2H), 7.2 (m, 2H), 7.25-7.35 (m, 3H), 7.5-7.6(m, 4H); MS [M-CF₃COO]⁺: 552.

EXAMPLE 561-[3-(3-Cyanophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 18 mg, 17%. ¹H-NMR (DMSO-d6): δ 1.65-2.1 (m,6H), 2.35 (m, 1H), 3.2 (m, 1H), 3.3-3.55 (m, 6H), 3.95 (m, 1H), 4.15 (t,2H), 5.25 (m, 1H), 7.0 (m, 2H), 7.18 (m, 2H), 7.3 (d, 1H), 7.45 (m, 2H),7.55 (m, 4H); MS [M-CF₃COO]⁺: 509.

EXAMPLE 571-[3-(4-Cyanophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 180 mg, 53%. ¹H-NMR (DMSO-d6): δ 1.65-2.2 (m,6H), 2.3 (m, 1H), 3.2 (m, 1H), 3.3-3.55 (m, 6H), 3.95 (m, 1H), 4.15 (t,2H), 5.25 (m, 1H), 7.0 (m, 2H), 7.1 (d, 2H), 7.15 (m, 2H), 7.5 (m, 2H),7.8 (d, 2H); MS [M-Br]⁺: 509; mp 158° C.

EXAMPLE 583(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(3-methoxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 19 mg, 18%. ¹H-NMR (DMSO-d6): δ 1.65-2.15 (m,6H), 2.15 (m, 1H), 3.2 (m, 1H), 3.3-3.5 (m, 6H), 3.75 (s, 3H), 3.95 (m,1H), 4.0 (t, 2H), 5.25 (m, 1H), 6.55 (m, 3H), 7.0 (m, 2H), 7.2 (m, 3H),7.55 (m, 3H); MS [M-CF₃COO]⁺: 514.

EXAMPLE 593(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(4-methoxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 14 mg, 13%. ¹H-NMR (DMSO-d6): δ 1.65-2.15 (m,6H), 2.35 (m, 1H), 3.2 (m, 1H), 3.3-3.55 (m, 6H), 3.7 (s, 3H), 3.9-4.0(m, 3H), 5.25 (m, 1H), 6.9 (s, 4H), 7.0 (m, 2H), 7.15 (m, 2H), 7.5 (m,3H); MS [M-CF₃COO]⁺: 514.

EXAMPLE 601-[3-(Benzo[1,3]dioxol-5-yloxy)propyl]-3(R)-(2-hydroxy-2,2-dithienn-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 19 mg, 17%. ¹H-NMR (DMSO-d6): δ 1.65-2.15 (m,7H), 2.3 (m, 1H), 3.15 (m, 1H), 3.25-3.5 (m, 6H), 3.9-4.0 (m, 3H), 5.25(m, 1H), 5.95 (s, 2H), 6.4 (d, 1H), 6.65 (s, 1H), 6.85 (d, 1H), 7.0 (m,2H), 7.2 (m, 2H), 7.5 (m, 3H); MS [M-CF₃COO]⁺: 528.

EXAMPLE 611-[3-(2-Carbamoylphenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 18 mg, 16%. ¹H-NMR (DMSO-d6): δ 1.65-2.0 (m,4H), 2.2 (m, 2H), 2.3 (m, 1H), 3.15 (m, 1H), 3.25-3.55 (m, 6H), 3.95 (m,1H), 4.15 (t, 2H), 5.25 (m, 1H), 7.0-7.2 (m, 6H), 7.4-7.6 (m, 6H), 7.7(d, 1H); MS [M-CF₃COO]⁺: 527.

EXAMPLE 621-[3-(3-Dimethylaminophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 19 mg, 17%. ¹H-NMR (DMSO-d6): δ 1.65-2.15 (m,6H), 2.3 (m, 1H), 2.85 (s, 6H), 3.1-3.5 (m, 7H), 3.85-4.0 (m, 3H), 5.25(m, 1H), 6.2 (m, 1H), 6.25 (d, 1H), 6.35 (d, 1H), 7.0 (m, 2H), 7.1 (t,1H), 7.2 (m, 2H), 7.5 (m, 3H); MS [M-CF₃COO]⁺: 527.

EXAMPLE 633(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(4-nitrophenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 22 mg, 20%. ¹H-NMR (DMSO-d6): δ 1.65-2.0 (m,4H), 2.2 (m, 2H), 2.3 (m, 1H), 3.2 (m, 1H), 3.3-3.5 (m, 6H), 3.95 (m,1H), 4.2 (t, 2H), 5.25 (m, 1H), 7.0 (m, 2H), 7.15 (m, 4H), 7.5 (m, 3H),8.15 (d, 2H); MS [M-CF₃COO]⁺: 529.

EXAMPLE 643(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(3-nitrophenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 18 mg, 16%. ¹H-NMR (DMSO-d6): δ 1.65-2.2 (m,6H), 2.3 (m, 1H), 3.15-3.55 (m, 7H), 3.95 (m, 1H), 4.2 (t, 2H), 5.25 (m,1H), 7.0 (m, 2H), 7.2 (m, 2H), 7.45 (dd, 1H), 7.55 (m, 3H), 7.6 (t, 1H),7.75 (s, 1H), 7.85 (d, 1H); MS [M-CF₃COO]⁺: 529.

EXAMPLE 651-[3-(4-Acetylaminophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 19 mg, 17%. ¹H-NMR (DMSO-d6): δ 1.65-2.15 (m,6H), 2.0 (s, 3H), 2.3 (m, 1H), 3.2 (m, 1H), 3.3-3.55 (m, 6H), 3.9-4.0(m, 3H), 5.25 (m, 1H), 6.85 (d, 2H), 7.0 (m, 2H), 7.2 (m, 2H), 7.5 (m,5H), 9.8 (s, 1H); MS [M-CF₃COO]⁺: 541.

EXAMPLE 663(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(3-methoxycarbonylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title-compound was synthesised according to methods c and b. Theyield of final step was 18 mg, 16%. ¹H-NMR (DMSO-d6): δ 1.65-2.2 (m,6H), 2.3 (m, 1H), 3.2 (m, 1H), 3.3-3.5 (m, 6H), 3.85 (s, 3H), 3.95 (m,1H), 4.1 (t, 2H), 5.25 (m, 1H), 7.0 (m, 2H), 7.15 (m, 2H), 7.25 (dd,1H), 7.45-7.6 (m, 6H); MS [M-CF₃COO]⁺: 542.

EXAMPLE 673(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-{3-[4-(3-hydroxypropyl)phenoxy]propyl}-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 14 mg, 13%. ¹H-NMR (DMSO-d6): δ 1.6-2.15 (m,8H), 2.3 (m, 1H), 2.55 (t, 2H), 3.2 (m, 1H), 3.25-3.55 (m, 9H), 3.85-4.0(m, 3H), 4.45 (t, OH), 5.25 (m, 1H), 7.85 (d, 2H), 7.0 (m, 2H), 7.1 (d,2H), 7.15 (m, 2H), 7.5 (m, 2H); MS [M-CF₃COO]⁺: 542.

EXAMPLE 683(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(2-hydroxymethylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 16 mg, 15%. ¹H-NMR (DMSO-d6): δ 1.7-2.2 (m, 6H),2.35 (m, 1H), 3.1-3.5 (m, 7H), 3.9-4.05 (m, 3H), 4.5 (m, 2H), 5.0 (t,OH), 5.15 (m, 1H), 6.9-7.05 (m, 4H), 7.2 (m, 2H), 7.4 (d, 1H), 7.5 (m,3H); MS [M-CF₃COO]⁺: 514.

EXAMPLE 693(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(3-hydroxymethylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane; trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 16 mg, 15%. ¹H-NMR (DMSO-d6): δ 1.7-2.2 (m, 6H),2.35 (m, 1H), 3.15-3.5 (m, 7H), 3.9 (m, 1H), 4.05 (t, 2H), 4.45 (d, 2H),5.25 (m, 2H), 6.8 (d, 1H), 6.9 (m, 2H), 7.2 (m, 2H), 7.25 (t, 1H), 7.5(m, 3H); MS [M-CF₃COO]⁺: 514.

EXAMPLE 703(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(4-hydroxymethylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 17 mg, 16%. ¹H-NMR (DMSO-d6) δ 1.65-2.2 (m, 6H),2.3 (m, 1H), 3.15-3.55 (m, 7H), 3.9-4.05 (m, 3H), 4.4 (d, 2H), 5.1 (t,OH), 5.25 (t, 1H), 6.9 (d, 2H), 7.0 (m, 2H), 7.2 (m, 2H), 7.25 (d, 2H),7.5 (m, 3H); MS [M-CF₃COO]⁺: 514.

EXAMPLE 713(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(2-hydroxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 24 mg, 19%. ¹H-NMR (DMSO-d6): δ 1.65-2.15 (m,6H), 2.35 (m, 1H), 3.2 (m, 1H), 3.25-3.55 (m, 6H), 3.95 (m, 1H), 4.0 (t,2H), 5.25 (m, 1H), 6.7-6.85 (m, 3H), 6.95 (d, 1H), 7.0 (m, 2H), 7.2 (m,2H), 7.5 (m, 3H), 8.85 (s, OH); MS [M-CF₃COO]⁺: 500.

EXAMPLE 723(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(4-hydroxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 16 mg, 15%. ¹H-NMR (DMSO-d6): δ 1.65-2.1 (m,6H), 2.3 (m, 1H), 3.2 (m, 1H), 3.25-3.5 (m, 6H), 3.95 (m, 3H), 5.25 (m,1H), 6.7 (d, 2H), 6.75 (d, 2H), 7.0 (m, 2H), 7.2 (m, 2H), 7.5 (t, 3H),9.0 (s, OH); MS [M-CF₃COO]⁺: 500.

EXAMPLE 733(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(3-hydroxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 16 mg, 15%. ¹H-NMR (DMSO-d6): δ 1.65-2.15 (m,6H), 2.3 (m, 1H), 3.2 (m, 1H), 3.3-3.55 (m, 6H), 3.9-4.0 (m, 3H), 5.25(m, 1H), 6.9-6.0 (m, 3H), 7.0-7.1 (m, 3H), 7.2 (m, 2H), 7.5 (m, 3H),9.45 (s, OH); MS [M-CF₃COO]⁺: 500.

EXAMPLE 743(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-pyrrol-1-ylpropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 21 mg, 22%. ¹H-NMR (DMSO-d6): δ 1.65-1.8 (m,2H), 1.8-2.0 (m, 2H), 2.0-2.15 (m, 2H), 2.3 (m, 1H), 3.05-3.2 (m, 3H),3.2-3.5 (m, 4H), 3.8-3.95 (m, 3H), 5.2 (m, 1H), 6.05 (t, 2H), 6.75 (t,2H), 7.0 (t, 2H), 7.15 (d, 2H), 7.55 (m, 3H); MS [M-CF₃COO]⁺: 457.

EXAMPLE 753(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(4-oxo-4-thien-2-ylbutyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 18 mg, 17%. ¹H-NMR (DMSO-d6): δ 1.7-1.85 (m,2H), 1.9-2.1 (m, 4H), 2.3 (m, 1H), 3.1 (t, 2H), 3.15-3.55 (m, 7H), 3.95(m, 1H), 5.25 (m, 1H), 7.0 (t, 2H), 7.4 (d, 2H), 7.25 (t, 1H), 7.55 (m,3H), 7.95 (d, 1H), 8.05 (d, 1H); MS [M-CF₃COO]⁺: 502.

EXAMPLE 763(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[3-(1-methyl-[1H]-imidazol-2-ylsulfanyl)propyl]-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 26 mg, 25%. ¹H-NMR (DMSO-d6): δ 1.7 (m, 2H),1.85-2.05 (m, 4H), 2.3 (m, 1H), 3.25-3.5 (m, 7H), 3.6 (s, 3H), 3.9 (m,1H), 4.2 (t, 2H), 5.2 (m, 1H), 7.0 (m, 3H), 7.15 (m, 2H), 7.3 (m, 1H),7.5 (m, 3H); MS [M-CF₃COO]⁺: 504.

EXAMPLE 773(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(2-thien-2-ylethyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 430 mg, 54%. ¹H-NMR (DMSO-d6): δ 1.6-1.8 (m,2H), 2.3 (m, 1H), 3.15-3.3 (m, 4H), 3.35-3.55 (m, 5H), 3.95 (m, 1H),5.25 (m, 1H), 7.0 (m, 4H), 7.15 (m, 2H), 7.4-7.5 (m, 4H); MS [M-Br]⁺:460; mp 206° C.

EXAMPLE 783(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 600 mg, 77%. ¹H-NMR (DMSO-d6): δ 1.6-1.8 (m,2H), 1.85-2.1 (m, 4H), 2.3 (m, 1H), 2.8 (t, 2H), 3.1-3.5 (m, 7H), 3.9(m, 1H), 5.2 (m, 1H), 6.9-7.05 (m, 4H), 7.15 (m, 2H), 7.4 (d, 1H), 7.5(m, 3H); MS [M-Br]⁺: 474; mp 138° C.

EXAMPLE 791-[3-(Benzothiazol-2-yloxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 23 mg, 21%. ¹H-NMR (DMSO-d6): δ 1.65-2.1 (m,6H), 2.3 (m, 1H), 3.15 (m, 1H), 3.25-3.5 (m, 6H), 3.85 (m, 1H), 4.0 (t,2H), 5.2 (m, 1H), 7.0 (t, 2H), 7.15 (m, 2H), 7.25 (m, 1H), 7.45 (m, 5H),7.7 (d, 1H); MS [M-CF₃COO]⁺: 541.

EXAMPLE 801-(3-Benzyloxypropyl)-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]-octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 16 mg, 15%. ¹H-NMR (DMSO-d6): δ 1.65 (m, 2H),1.9 (m, 4H), 2.3 (m, 1H), 3.1-3.4 (m, 7H), 3.5 (t, 2H), 3.9 (m, 1H), 3.9(s, 2H), 5.2 (m, 1H), 7.0 (m, 2H), 7.15 (m, 2H), 7.35 (m, 5H), 7.5 (m,3H); MS [M-CF₃COO]⁺: 498.

EXAMPLE 813(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-[6-(4-phenylbutoxy)hexyl]-1-azoniabicyclo[2.2.2]octane; bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 560 mg, 60%. ¹H-NMR (CDCl₃): δ 1.2-1.75 (m,16H), 1.8-2.1 (m, 4H), 2.4 (m, 1H), 2.6 (t, 2H), 3.3-3.75 (m, 11H), 4.2(m, 1H), 5.3 (m, 1H), 6.0 (bs, OH), 6.95 (m, 2H), 7.15-7.3 (m, 9H); MS[M-Br]⁺: 582.

EXAMPLE 823(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(4-phenoxybutyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 240 mg, 30%. ¹H-NMR (DMSO-d6/CDCl₃): δ 1.8-1.95(m, 6H), 2.1 (m, 2H), 2.45 (m, 1H), 3.18 (m, 1H), 3.5-3.8 (m, 6H), 4.0(t, 2H), 4.15 (m, 1H) 5.15 (m, 1H), 6.7 (s, OH), 6.9 (m, 5H), 7.15 (d,1H), 7.25 (m, 5H); MS [M-Br]⁺: 498; mp 161° C.

EXAMPLE 833(R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 380 mg, 50%. ¹H-NMR (DMSO-d6): δ 1.85 (m, 2H),2.05 (m, 2H), 2.4 (m, 1H), 3.6-4.1 (m, 7H), 4.35 (m, 3H), 5.25 (m, 1H),6.0 (bs, OH), 6.9 (m, 4H), 7.0 (t, 1H), 7.1 (dd, 2H), 7.2 (dd, 2H), 7.3(t, 2H); MS [M-Br]⁺: 470; mp 48° C.

EXAMPLE 841-(2-Benzyloxyethyl)-3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 17 mg, 17%. ¹H-NMR (DMSO-d6): δ 1.65-2.0 (m,4H), 2.3 (m, 1H), 3.2-3.55 (m, 7H), 3.85 (m, 2H), 4.5 (s, 2H), 5.25 (m,1H), 7.0 (t, 2H), 7.15 (t, 2H), 7.3-7.4 (m, 4H), 7.5 (m, 3H); MS[M-CF₃COO]⁺: 484.

EXAMPLE 853(S)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 600 mg, 54%. ¹H-NMR (DMSO-d6/CDCl₃): δ 1.85-2.3(m, 6H), 2.5 (m, 1H), 3.3 (m, 1H), 3.4 (d, 1H), 3.5-3.7 (m, 5H), 4.05(t, 2H), 4.2 (m, 1H), 5.25 (m, 1H), 6.85 (d, 2H), 7.0 (m, 3H), 7.15 (m,2H), 7.2 (d, 1H), 7.3 (m, 4H); MS [M-Br]⁺: 484; mp 230° C.

EXAMPLE 864-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods f and a. Theyield of final step was 290 mg, 60%. ¹H-NMR (DMSO-d6): δ 2.15 (m, 2H),2.35 (m, 6H), 3.35 (m, 2H), 3.65 (m, 6H), 4.05 (t, 2H), 6.9-7.05 (m,5H), 7.1 (m, 2H), 7.3 (m, 3H), 7.55 (m, 2H); MS [M-Br]⁺: 484; mp 1681 C.

EXAMPLE 874-(2-Hydroxy-2,2-dithien-2-yl-acetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods f and a. Theyield of final step was 260 mg, 57%. ¹H-NMR (DMSO-d6): δ 2.35 (m, 6H),3.0 (m, 2H), 3.4 (m, 2H), 3.75 (m, 6H), 7.0 (m, 2H), 7.3-7.5 (m, 6H),7.55 (m, 2H); MS [M-Br]⁺: 454; mp 1951 C.

EXAMPLE 881-(3-phenoxypropyl)-3(R)-(2,2-dithien-2-ylpropionyloxy)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 390 mg, 92%. ¹H-NMR (DMSO-d6): δ 1.65-2.20 (m,6H), 2.10 (s, 3H), 2.30 (bs, 1H), 3.10 (m, 1H), 3.30-3.60 (m, 6H),3.95-4.10 (m, 3H), 5.20 (m, 1H), 6.90-7.05 (m, 5H), 7.05-7.10 (m, 2H),7.25-7.35 (m, 2H), 7.50 (m, 2H); MS [M-Br]⁺: 482; mp 170° C.

EXAMPLE 893(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 300 mg, 76%. ¹H-NMR (DMSO-d6): δ 1.6 (m, 1H),1.75 (m, 1H), 1.8-2.0 (m, 2H), 2.0-2.2 (m, 2H), 2.3 (m, 1H), 3.15 (m,1H), 3.3-3.6 (m, 6H), 3.9 (m, 1H), 4.05 (t, 2H), 5.2 (m, 1H), 6.75 (s,OH), 6.95 (m, 3H), 7.15 (m, 2H), 7.3 (t, 2H), 7.4-7.5 (m, 4H); MS[M-Br]⁺: 484; mp 2191 C.

EXAMPLE 903(R)-(2-Hydroxy-2,2-dithienyl-3-ylacetoxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 300 mg, 77%. ¹H-NMR (DMSO-d6): δ 1.5-1.6 (m,1H), 1.6-1.75 (m, 1H), 1.8-2.1 (m, 4H), 2.25 (m, 1H), 2.8 (t, 2H),3.05-3.5 (m, 7H), 3.8-3.95 (m, 1H), 5.15 (m, 1H), 6.75 (s, OH), 6.9-7.0(m, 2H), 7.1 (m, 2H), 7.35-7.55 (m, 5H); MS [M-Br]⁺: 474; mp 1921 C.

EXAMPLE 913(R)-(2-Hydroxy-2,2-dithien-3-yl-acetoxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 63 mg, 48%. ¹H-NMR (DMSO-d6): δ 1.5-1.7 (m, 1H),1.7-1.85 (m, 1H), 1.9-2.1 (m, 2H), 2.3 (m, 1H), 2.9-3.1 (m, 2H),3.15-3.6 (m, 7H), 3.9-4.0 (m, 1H), 5.2 (m, 1H), 6.8 (s, OH), 7.1 (m,2H), 7.25-7.35 (m, 5H), 7.4 (m, 2H), 7.5 (m, 2H); MS [M-CF3COO]⁺: 454.

EXAMPLE 923(R)-(2-Hydroxy-2,2-dithien-3-yl-acetoxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 75 mg, 55%. ¹H-NMR (DMSO-d6): δ 1.5-2.0 (m, 6H),2.25 (m, 1H), 2.5-2.6 (m, 2H), 3.05-3.6 (m, 8H), 3.8-3.9 (m, 1H), 5.15(m, 1H), 6.75 (s, OH), 7.1 (d, 2H), 7.2-7.35 (m, 5H), 7.4 (m, 2H), 7.5(m, 2H); MS [M-CF3COO]⁺: 468.

EXAMPLE 933(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 68 mg, 48%. ¹H-NMR (DMSO-d6): δ 1.5-1.8 (m, 6H),1.8-2.0 (m, 2H), 2.25 (m, 1H), 2.6 (m, 2H), 3.05 (m, 1H), 3.15-3.45 (m,6H), 3.85 (m, 1H), 5.15 (m, 1H), 6.75 (s, OH), 7.1 (d, 2H), 7.2 (m, 2H),7.3 (m, 3H), 7.4 (m, 2H), 7.5 (m, 2H); MS [M-CF3COO]⁺: 482.

EXAMPLE 943(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(2-thien-2-ylethyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 65 mg, 49%. ¹H-NMR (DMSO-d6): δ 1.5-1.65 (m,1H), 1.65-1.78 (m, 1H), 1.85-2.05 (m, 2H), 2.3 (m, 1H), 3.1-3.6 (m, 9H),3.95 (m, 1H), 5.2 (m, 1H), 6.75 (s, OH), 7.0 (m, 2H), 7.15 (m, 2H), 7.45(m, 3H), 7.5 (m, 2H); MS [M-CF3COO]⁺: 460.

EXAMPLE 953(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(4-phenoxybutyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 63 mg, 43%. ¹H-NMR (DMSO-d6): δ 1.5-2.0 (m, 8H),2.3 (m, 1H), 3.1 (m, 1H), 3.2-3.5 (m, 6H), 3.85 (m, 1H), 4.0 (m, 2H),5.2 (m, 1H), 6.75 (s, OH), 6.95 (m, 3H), 7.1 (d, 2H), 7.2 (m, 2H), 7.3(t, 2H), 7.45 (m, 2H), 7.5 (m, 2H); MS [M-CF3COO]⁺: 498.

EXAMPLE 963(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 72 mg, 52%. ¹H-NMR (DMSO-d6): δ 1.55-1.65 (m,1H), 1.7-1.8 (m, 1H), 1.85-2.05 (m,2H), 2.3 (m, 1H), 3.2-3.6 (m, 5H),3.7 (m, 2H), 4.05 (m, 1H), 4.4 (m, 2H), 5.2 (m, 1H), 6.75 (s, OH),6.95-7.05 (m, 3H), 7.1 (d, 2H), 7.3-7.5 (m, 6H); MS [M-CF3COO]⁺: 470.

EXAMPLE 971-[3-(4-Fluorophenoxy)propyl]-3(R)-(2-hydroxy-2,2-dithien-3-ylacetoxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 79 mg, 54%. ¹H-NMR (DMSO-d6): δ 1.55-1.65 (m,1H), 1.7-1.8 (m, 1H), 1.85-2.0 (m, 2H), 2.05-2.2 (m, 2H), 2.3 (m, 1H),3.1-3.2 (m, 1H), 3.25-3.55 (m, 6H), 3.85-3.95 (m, 1H), 4.0 (t, 2H), 5.2(m, 1H), 6.75 (s, OH), 6.95 (m, 2H), 7.15 (m, 4H), 7.4 (m, 2H), 7.5 (m,2H); MS [M-CF3COO]⁺: 502.

EXAMPLE 983(R)-(2-Hydroxy-2,2-dithien-3-ylacetoxy)-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 24 mg, 17%. ¹H-NMR (DMSO-d6): δ 1.8-2.05 (m,4H), 2.3 (m, 1H), 3.15 (m, 1H), 3.3-3.5 (m, 4H), 3.9 (m, 1H), 4.05 (m2H), 5.25 (m, 1H), 6.35 (m, 1H), 6.75 (s, OH), 6.85 (t, 1H), 7.1 (m,2H), 7.3-7.5 (m, 5H), 7.55 (m, 4H); MS [M-CF3COO]⁺: 502.

EXAMPLE 991-(3-phenylallyl)-3(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 400 mg, 93%. ¹H-NMR (DMSO-d6): δ 1.35-1.50 (m,1H), 1.60-1.75 (m, 1H), 1.75-1.95 (m, 2H), 2.10 (m, 1H), 2.85 (m, 1H),3.10 (d, 1H), 3.20-3.50 (m, 3H), 3.85 (m, 1H), 4.0 (dd, 2H), 5.05 (m,1H), 6.40 (dd, 1H), 6.80-6.90 (d, 1H), 6.85 (s, OH), 7.20-7.50 (m, 7H),7.60 (m, 4H), 7.80 (m, 2H); MS [M-Br]⁺: 452; mp 146° C.

EXAMPLE 1003(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-(3-phenoxy-propyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 690 mg, 83%. ¹H-NMR (DMSO-d6): δ 1.47 (m, 1H),1.68 (m, 1H), 1.87 (m, 2H), 2.1 (m, 3H), 2.89 (m, 1H), 3.15 (d, 1H), 3.4(m, 5H), 3.9 (m, 1H), 4.0 (m, 2H), 5.04 (m, 1H), 6.85 (s, OH), 6.97 (m,3H), 7.35 (m, 4H), 7.45 (m, 2H), 7.65 (m, 2H), 7.85 (m, 2H); MS [M-Br]⁺:470; mp 108° C.

EXAMPLE 1013(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 170 mg, 74%. ¹H-NMR (DMSO-d6): δ 1.45 (m, 1H),1.65 (m, 1H), 1.85 (m, 2H), 2.1 (m, 1H), 2.9 (m, 3H), 3.15 (m, 1H),3.3-3.5 (m, 5H), 3.85 (m, 1H), 5.05 (m, 1H), 6.85 (s, OH), 7.2-7.4 (m,7H), 7.45 (t, 2H), 7.55 (d, 1H), 7.65 (d, 1H), 7.85 (d, 2H); MS [M-Br]⁺:440; mp 118° C.

EXAMPLE 1023(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 460 mg, 96%. ¹H-NMR (DMSO-d6): δ 1.42 (m, 1H),1.66 (m, 1H), 1.80-1.88 (m, 2H), 2.08 (m, 1H), 2.93 (m, 1H), 3.25-3.60(m, 4H), 3.65 (m, 2H), 3.95 (m, 1H), 4.35 (m 2H), 5.02 (m, 1H), 6.85 (s,1H, OH), 6.97 (d, 2H), 7.04 (t, 1H), 7.20-7.45 (m, 6H), 7.55-7.60 (t,2H), 7.80 (d, 2H); MS [M-Br]⁺: 456; mp 140° C.

EXAMPLE 1033(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-(4-oxo-4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 15 mg, 15%. ¹H-NMR (DMSO-d6): δ 1.45 (m, 1H),1.65 (m, 1H), 1.7-2.0 (m, 4H), 2.1 (m, 1H), 2.75 (m, 1H), 3.0-3.2 (m4H), 3.25-3.4 (m, 4H), 3.85 (m, 1H), 5.05 (m, 1H), 6.85 (s, OH), 7.35(t, 2H), 7.45 (t, 2H), 7.55-7.7 (m, 5H), 7.85 (d, 2H), 8.0 (d, 2H); MS[M-CF₃COO]⁺: 482.

EXAMPLE 1041-[3-(4-Fluorophenoxy)propyl]-3(R)-(9-hydroxy-9[H]-fluorene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;chloride

The title compound was synthesised according to methods c and a. Theyield of final step was 440 mg, 94%. ¹H-NMR (DMSO-d6): δ 1.4 (m, 1H),1.65 (m, 2H), 1.7-1.95 (m, 2H), 2.0-2.1 (m, 3H), 2.8 (m, 1H), 3.1 (d,1H), 3.2-3.4 (m, 5H), 3.8 (m, 1H), 4.0 (t, 2H), 5.0 (m, 1H), 6.85 (s,OH), 6.95 (m, 2H), 7.15 (t, 2H), 7.35 (t, 2H), 7.45 (t, 2H), 7.55 (d,1H), 7.65 (d, 1H), 7.85 (d, 2H); MS [M-Br]⁺: 488; mp 142° C.

EXAMPLE 1051-[3-(2,4-Difluorophenoxy)propyl]-3(R)-(9-hydroxy-9[H]-fluorene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 14 mg, 13%. ¹H-NMR (DMSO-d6): δ 1.4 (m, 1H),1.6-1.9 (m, 3H), 2.1 (m, 3H), 2.8 (m, 1H), 3.1 (d, 1H), 3.2-3.4 (m, 5H),3.85 (m, 1H), 4.05 (t, 2H), 5.0 (m, 1H), 6.85 (s, OH), 7.05 (t, 1H),7.15-7.4 (m, 4H), 7.45 (t, 2H), 7.55 (d, 1H), 7.65 (d, 1H), 7.85 (d,2H); MS [M-CF₃COO]⁺: 506.

EXAMPLE 1063(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-(3-phenylaminopropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 14 mg, 15%. ¹H-NMR (DMSO-d6): δ 1.4 (m, 1H), 1.6(m, 1H), 1.8 (m, 4H), 2.05 (m, 1H), 2.7 (m, 1H), 3.0 (m, 3H), 3.2-3.4(m, 6H), 3.8 (m, 1H), 5.0 (m, 1H), 5.6 (t, NH), 6.55 (m, 3H), 6.85 (s,OH), 7.1 (t, 2H), 7.35 (dd, 2H), 7.45 (dd, 2H), 7.55 (dd, 2H), 7.8 (d,2H); MS [M-CF₃COO]⁺: 469.

EXAMPLE 1073(R)-(9-Hydroxy-9[H]-fluorene-9-carbonyloxy)-1-[3-(4-hydroxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 15 mg, 15%. ¹H-NMR (DMSO-d6): δ 1.4 (m, 1H), 1.6(m, 1H), 1.7-1.9 (m, 2H), 1.95-2.05 (m, 2H), 2.1 (m, 1H), 2.8 (m, 1H),3.1 (d, 1H) 3.25-3.4 (m, 5H), 3.8-3.9 (m, 3H), 5.0 (m, 1H), 6.7 (d, 2H),6.75 (d, 2H), 6.85 (s, OH), 7.35 (t, 2H), 7.45 (t, 2H), 7.55 (d, 1H),7.65 (d, 1H), 7.85 (d, 2H), 9.0 (s, OH); MS [M-CF₃COO]⁺: 486.

EXAMPLE 1081-(2-Benzyloxyethyl)-3(R)-(9-hydroxy-9[H]-fluorene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 470 mg, 96%. ¹H-NMR (DMSO-d6): δ 1.4 (m, 1H),1.65 (m, 1H), 1.7-1.9 (m, 2H), 2.1 (m, 1H), 2.9 (m, 1H), 3.15-3.5 (m,6H), 3.75 (m, 2H), 3.85 (m, 1H), 4.5 (s, 2H), 5.0 (m, 1H), 6.85 (s, OH),7.3-7.5 (m, 9H), 7.55 (m, 2H), 7.8 (d, 2H); MS [M-Br]⁺: 470; mp 86° C.

EXAMPLE 1093(R)-(9-Hydroxy-9H-fluorene-9-carbonyloxy)-1-(3-thienyl-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 180 mg, 70%. ¹H-NMR (DMSO-d6): δ 1.37 (m, 1H),1.62 (m, 1H), 1.75-1.95 (m, 4H), 2.06 (m, 1H), 2.72 (m, 1H), 2.80 (m,2H), 3.02-3.06 (m, 1H), 3.15-3.20 (m, 2H), 3.25-3.40 (m, 3H), 3.80 (m,1H), 5.0 (m, 1H), 6.85 (s, 1H, OH), 6.95-7.0 (m, 2H), 7.25-7.50 (m, 5H),7.55-7.65 (m, 2H), 7.85 (d, 2H); MS [M-Br]⁺: 460; mp 140° C.

EXAMPLE 1103(R)-(9-Hydroxy-9H-fluorene-9-carbonyloxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 80 mg, 40%. ¹H-NMR (DMSO-d6) δ 1.35 (m, 1H), 1.6(m, 1H), 1.7-1.90 (m, 2H), 2.05 (m, 1H), 2.5 (m, 2H), 2.7 (m, 1H), 3.0(m, 1H), 3.15 (m, 2H), 3.2-3.4 (m, 3H), 3.75 (m, 1H), 5.0 (m, 1H), 6.85(s, OH), 7.20-7.50 (m, 9H), 7.55 (dd, 2H), 7.85 (d, 2H); MS [M-CF3COO]⁺:454.

EXAMPLE 1113(R)-(9-Hydroxy-9H-fluorene-9-carbonyloxy)-1-(4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 74 mg, 35%. ¹H-NMR (DMSO-d6): δ 1.35 (m, 1H),1.45-1.65 (m, 5H), 1.7-1.90 (m, 2H), 2.05 (m, 1H), 2.55-2.75 (m, 3H),3.0 (m, 1H), 3.15-3.45 (m, 5H), 3.75 (m, 1H), 5.0 (m, 1H), 6.85 (s, OH),7.20 (m, 3H), 7.25-7.35 (m, 4H), 7.45-7.5 (m, 2H), 7.55-7.6 (dd, 2H),7.85 (d, 2H); MS [M-CF3COO]⁺: 468.

EXAMPLE 1123(R)-(9-Hydroxy-9H-fluorene-9-carbonyloxy-1-(2-thienyl-2-ylethyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 79 mg, 39%. ¹H-NMR (DMSO-d6): δ 1.4 (m, 1H),1.65 (m, 1H), 1.8-1.95 (m, 2H), 2.1 (m, 1H), 2.9 (m, 1H), 3.1-3.25 (m,4H), 3.15-3.45 (m, 5H), 3.85 (m, 1H), 5.05 (m, 1H), 6.85 (s, OH), 7.0(m, 2H), 7.35 (t, 2H), 7.45-7.5 (m, 3H), 7.55 (d, 1H), 7.65 (d, 1H),7.85 (d, 2H); MS[M-CF3COO]⁺: 446.

EXAMPLE 1133(R)-(9-Hydroxy-9H-fluorene-9-carbonyloxy)-1-(4-phenoxybutyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 72 mg, 33%. ¹H-NMR (DMSO-d6): δ 1.4 (m, 1H),1.55-1.9 (m, 7H), 2.05 (m, 1H), 2.7 (m, 1H), 3.0 (m, 1H), 3.15-3.5 (m,7H), 3.8 (m, 1H), 4.0 (m, 2H), 5.05 (m, 1H), 6.85 (s, OH), 6.95 (m, 3H),7.25-7.35 (m, 4H), 7.4-7.45 (m, 2H), 7.6 (dd, 2H), 7.85 (d, 2H); MS[M-CF3COO]⁺: 484.

EXAMPLE 1143(R)-(9-Methyl-9[H]-fluorene-9-carbonyloxy)-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 200 mg, 76%. ¹H-NMR (DMSO-d6): δ 1.54 (m, 1H),1.70-1.86 (m, 3H), 1.76 (s, 3H), 2.13 (m, 1H), 3.06 (m, 1H), 3.20-3.50(m, 4H), 3.86 (m, 1H), 4.05 (dd, 2H), 5.02 (m, 1H), 6.43 (dd, 1H), 6.86(d, 1H), 7.26-7.46 (m, 7H), 7.58-7.65 (m, 3H), 7.70-7.72 (m, 1H),7.87-7.90 (m, 2H); MS [M-Br]⁺: 450; mp 234° C.

EXAMPLE 1153(R)-(9-Methyl-9[H]-fluorene-9-carbonyloxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 210 mg, 66%. ¹H-NMR (DMSO-d6): δ 1.55 (m, 1H),1.60-2.0 (m, 3H), 1.76 (s, 3H), 2.12 (m, 1H), 3.10-3.25 (m, 1H),3.40-3.80 (m, 6H), 4.0 (m, 1H), 4.41 (m, 2H), 4.98 (m, 1H), 6.98-7.05(m, 3H), 7.27-7.46 (m, 6H), 7.63-7.71 (m, 2H), 7.87-7.90 (m, 2H); MS[M-Br]⁺: 454; mp 202° C.

EXAMPLE 1163(R)-(9-Methyl-9[H]-fluorene-9-carbonyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 210 mg, 61%. ¹H-NMR (DMSO-d6): δ 1.55 (m, 1H),1.60-2.0 (m, 3H), 1.78 (s, 3H), 2.0-2.20 (m, 3H), 3.0-3.10 (m, 1H),3.25-3.53 (m, 6H), 3.86 (m, 1H), 4.03 (m, 2H), 4.98 (m, 1H), 6.95-7.0(m, 3H), 7.30-7.48 (m, 6H), 7.65-7.92 (m, 4H); MS [M-Br]⁺: 468; mp 204°C.

EXAMPLE 1173(R)-(9-Methyl-9[H]-fluorene-9-carbonyloxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 18 mg, 19%. ¹H-NMR (DMSO-d6): δ 1.55 (m, 1H),1.65-1.95 (m, 3H), 1.75 (s, 3H), 2.15 (m, 1H), 2.9-3.1 (m, 4H),3.25-3.55 (m, 5H), 3.85 (m, 1H), 5.05 (m, 1H), 7.25-7.55 (m, 9H), 7.65(d, 1H), 7.75 (d, 1H), 7.95 (d, 2H); MS [M-CF₃COO]⁺: 438.

EXAMPLE 1183(R)-(9-Methyl-9[H]-fluorene-9-carbonyloxy)-1-(4-oxo-4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 19 mg, 19%. ¹H-NMR (DMSO-d6): δ 1.55 (m, 1H),1.65-2.05 (m, 5H), 1.75 (s, 3H), 2.1 (m, 1H) 3.0 (m, 1H), 3.1-3.5 (m,8H), 3.85 (m, 1H), 7.35-7.5 (m, 4H), 7.55 (t, 2H), 7.65 (t, 2H), 7.7 (d,1H), 7.9 (d, 2H), 8.0 (d, 2H); MS [M-CF₃COO]⁺: 480.

EXAMPLE 1191-[3-(4-Fluorophenoxy)propyl]-3(R)-(9-methyl-9[H]-fluorene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 23 mg, 23%. ¹H-NMR (DMSO-d6): δ 1.55 (m, 1H),1.65-1.95 (m, 3H), 1.75 (s, 3H), 2.05-2.15 (m, 3H), 3.0 (m, 1H),3.25-3.5 (m, 6H), 3.85 (m, 1H), 4.0 (t, 2H), 5.0 (m, 1H), 6.95 (m, 2H),7.15 (t, 2H), 7.35-7.5 (m, 4H), 7.65 (d, 1H), 7.75 (d, 1H), 7.9 (d, 2H);MS [M-CF₃COO]⁺: 486.

EXAMPLE 1201-[3-(2,4-Difluorophenoxy)propyl]-3(R)-(9-methyl-9H-fluorene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 20 mg, 19%. ¹H-NMR (DMSO-d6): δ 1.55 (m, 1H),1.65-1.95 (m, 3H), 1.75 (s, 3H), 2.05-2.2 (m, 3H), 3.0 (m, 1H),3.25-3.55 (m, 6H), 3.85 (m, 1H), 4.1 (t, 2H), 5.0 (m, 1H), 7.05 (t, 1H),7.2-7.5 (m, 6H), 7.65 (d, 1H), 7.75 (d, 1H), 7.9 (d, 2H); MS[M-CF₃COO]⁺: 504.

EXAMPLE 1213(R)-(9-Methyl-9[H]-fluorene-9-carbonyloxy)-1-(3-phenylaminopropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 19 mg, 19%. ¹H-NMR (DMSO-d6): δ 1.55 (m, 1H),1.65-1.95 (m, 5H), 1.75 (s, 3H), 2.1 (m, 1H), 2.95 (m, 1H), 3.05 (m,2H), 3.15-3.45 (m, 6H), 3.8 (m, 1H), 5.0 (m, 1H), 5.65 (t, NH), 6.6 (m,3H), 7.1 (t, 2H), 7.35-7.55 (m, 4H), 7.65 (d, 1H), 7.75 (d, 1H), 7.9 (d,2H); MS [M-CF₃COO]⁺: 467.

EXAMPLE 1221-[3-(4-Hydroxyphenoxy)propyl]-3(R)-(9-methyl-9[H]-fluorene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 22 mg, 22%. ¹H-NMR (DMSO-d6): δ 1.55 (m, 1H),1.65-1.9 (m, 3H), 1.75 (s, 3H), 2.0-2.15 (m, 3H), 3.0 (m, 1H), 3.25-3.5(m, 6H), 3.8-3.95 (m, 3H), 5.0 (m, 1H), 6.7 (d, 1H), 6.75 (d, 1H),7.35-7.45 (m, 4H), 7.65 (d, 1H), 7.75 (d, 1H), 7.9 (d, 2H), 9.0 (s, OH);MS [M-CF₃COO]⁺: 484.

EXAMPLE 1231-(2-Benzyloxyethyl)-3(R)-(9-methyl-9[H]-fluorene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 17 mg, 17%. ¹H-NMR (DMSO-d6): δ 1.55 (m, 1H),1.65-1.95 (m, 4H), 1.75 (s, 3H), 2.15 (m, 1H), 3.1 (m, 1H), 3.3-3.55 (m,6H), 3.8-3.95 (m, 3H), 4.5 (s, 2H), 5.0 (m, 1H), 7.3-7.5 (m, 9H),7.6-7.7 (m, 2H), 7.9 (d, 2H); MS [M-CF₃COO]⁺: 468.

EXAMPLE 1243(R)-(9,10-Dihydroanthracene-9-carbonyloxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods d and a. Theyield of final step was 420 mg, 89%. ¹H-NMR (DMSO-d6): δ 1.55 (m, 1H),1.65-1.95 (m, 3H), 2.15 (m, 1H), 2.95 (m, 2H), 3.15 (m, 1H), 3.25-3.60(m, 6H), 3.85 (m, 1H), 3.95-4.15 (dd, 2H, J1=1.8 Hz, J2=4.2 Hz), 5.02(m, 1H), 5.25 (s, 1H), 7.25-7.43 (m, 11H), 7.48-7.55 (m, 2H); MS[M-Br]⁺: 438; mp 216° C.

EXAMPLE 1253(R)-(9,10-Dihydroanthracene-9-carbonyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods d and a. Theyield of final step was 450 mg, 82%. ¹H-NMR (DMSO-d6) δ 1.56 (m, 1H),1.65-1.95 (m, 3H), 2.05-2.15 (m, 3H), 3.10 (m, 1H), 3.20-3.50 (m, 6H),3.80 (m, 1H), 3.94-4.14 (m, 4H), 5.0 (m, 1H), 5.22 (s, 1H), 6.94-7.0 (m,3H), 7.25-7.35 (m, 6H), 7.40 (m, 2H), 7.54-7.47 (m, 2H); MS [M-Br]⁺:468; mp 157° C.

EXAMPLE 1261-(4-Phenylbutyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods d and a. Theyield of final step was 83 mg, 21%. ¹H-NMR (DMSO-d6): δ 1.50-2.0 (m,8H), 2.15 (m, 1H), 2.65 (m, 2H), 3.05-3.65 (m, 7H), 3.80 (m, 1H), 5.0(m, 1H), 5.30 (s, 1H), 7.10-7.45 (m, 11H), 7.45-7.60 (m, 2H); MS[M-Br]⁺: 468; mp 95° C.

EXAMPLE 1271-(2-Phenoxyethyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods d and a. Theyield of final step was 300 mg, 73%. ¹H-NMR (DMSO-d6): δ 1.70-2.0 (m,4H), 2.2 (m, 1H), 3.20-3.80 (m, 7H), 4.0 (m, 1H), 4.40 (m, 2H), 5.05 (m,1H), 5.30 (s, 1H), 7.0-7.10 (m, 7H), 7.30-7.45 (m, 4H), 7.45-7.55 (m,2H); MS [M-Br]⁺: 456; mp 200° C.

EXAMPLE 1281-(3-Phenoxypropyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods d and a. Theyield of final step was 350 mg, 83%. ¹H-NMR (DMSO-d6): δ 1.70-2.0 (m,4H), 2.0-2.25 (m, 3H), 3.15-3.65 (m, 7H), 3.85-3.95 (m, 1H), 3.95-4.10(m, 2H), 5.0 (m, 1H), 5.30 (s, 1H), 6.90-7.0 (m, 3H), 7.10-7.25 (m, 4H),7.25-7.40 (m, 4H), 7.40-7.60 (m, 2H); MS [M-Br]⁺: 470; mp 184° C.

EXAMPLE 1291-Phenethyl-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane; bromide

The title compound was synthesised according to methods d and a. Theyield of final step was 100 mg, 44%. ¹H-NMR (DMSO-d6): δ 1.65-2.0 (m,4H), 2.1 (m, 1H), 2.9-3.05 (m, 2H), 3.15-3.6 (m, 7H), 3.85 (m, 1H), 5.05(m, 1H), 5.3 (s, 1H)), 7.15-7.55 (m, 13H); MS [M-Br]⁺: 440.

EXAMPLE 1301-(4-Oxo-4-phenylbutyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods d and b. Theyield of final step was 16 mg, 15%. ¹H-NMR (DMSO-d6): δ 1.65-2.05 (m,6H), 2.1 (m, 1H), 3.1-3.55 (m, 9H), 3.8 (m, 1H), 5.05 (m, 1H), 5.25 (s,1H), 7.1-7.3 (m, 4H), 7.35 (t, 2H), 7.45-7.6 (m, 4H), 7.7 (d, 1H), 8.0(d, 1H); MS [M-CF₃COO]⁺: 482.

EXAMPLE 1311-[3-(4-Fluorophenoxy)propyl]-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane,trifluoroacetate

The title compound was synthesised according to methods d and b. Theyield of final step was 18 mg, 18%. ¹H-NMR (DMSO-d6): δ 1.7-2.1 (m, 6H),2.15 (m, 1H), 3.1-3.5 (m, 7H), 3.8 (m, 1H), 4.0 (t, 2H), 5.0 (m, 1H),5.3 (s, 1H), 6.95 (m, 2H), 7.1-7.3 (m, 6H), 7.4 (t, 2H), 7.5 (dd, 2H);MS [M-CF₃COO]⁺: 488.

EXAMPLE 1321-[3-(2,4-Difluorophenoxy)propyl]-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods d and b. Theyield of final step was 14 mg, 14%. ¹H-NMR (DMSO-d6): δ 1.65-1.95 (m,4H), 2.05-2.2 (m, 3H), 3.1-3.55 (m, 7H), 3.8 (m, 1H), 4.05 (t, 2H), 5.0(m, 1H), 5.3 (s, 1H), 7.05 (t, 1H), 7.1-7.55 (m, 10H); MS [M-CF₃COO]⁺:506.

EXAMPLE 1331-(3-Phenylaminopropyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods d and b. Theyield of final step was 17 mg, 17%. ¹H-NMR (DMSO-d6): δ 1.65-2.0 (m,6H), 2.15 (m, 1H), 3.0-3.5 (m, 9H), 1.75 (m, 1H), 5.0 (m, 1H), 5.3 (s,1H), 6.65 (t, NH), 6.55 (m, 3H), 0.5-7.3 (m, 6H), 7.35-7.55 (m, 4H); MS[M-CF₃COO]⁺: 469.

EXAMPLE 1341-[3-(4-Hydroxyphenoxy)propyl]-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods d and b. Theyield of final step was 21 mg, 20%. ¹H-NMR (DMSO-d6): δ 1.7-2.1 (m, 6H),2.15 (m, 1H), 3.1-3.5 (m, 7H), 3.7-3.95 (m, 3H), 5.0 (m, 1H), 5.3 (s,1H), 6.7 (d, 2H), 6.75 (d, 2H), 7.1-7.3 (m, 4H), 7.35-7.55 (m, 4H), 9.0(s, OH); MS [M-CF₃COO]⁺: 486.

EXAMPLE 1351-(2-Benzyloxyethyl)-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods d and b. Theyield of final step was 16 mg, 16%. ¹H-NMR (DMSO-d6): δ 1.65-1.95 (m,4H), 2.1 (m, 1H), 3.1-3.9 (m, 10H), 4.5 (s, 2H), 5.0 (m, 1H), 5.3 (s,1H), 7.15 (m, 4H), 7.3-7.5 (m, 7H), 7.55 (t, 2H); MS [M-CF₃COO]⁺: 470.

EXAMPLE 1363(R)-(9-Hydroxy-9[H]-xanthene-9-carbonyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 340 mg, 71%. ¹H-NMR (DMSO-d6): δ 1.30 (m, 1H),1.65 (m, 1H), 1.70-1.95 (m, 2H), 1.95-2.10 (m, 3H), 2.70 (m, 1H), 2.90(m, 1H), 3.2-3.5 (m, 5H), 3.80 (m, 1H), 4.0 (t, 2H), 5.05 (m, 1H),6.90-7.0 (m, 3H), 7.20-7.35 (m, 7H), 7.40-7.46 (m, 2H), 7.65-7.70 (m,2H); MS [M-Br]⁺: 486; mp 219° C.

EXAMPLE 1373(R)-(9-Hydroxy-9[H]-xanthene-9-carbonyloxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 290 mg, 64%. ¹H-NMR (DMSO-d6): δ 1.32 (m, 1H),1.65 (m, 1H), 1.70-1.95 (m, 2H), 2.1 (m, 1H), 2.75-2.90 (m, 3H), 3.05(m, 1H), 3.30-3.50 (m, 5H), 3.82 (m, 1H), 5.05 (m, 1H), 7.20-7.40 (m,10H), 7.40-7.50 (m, 2H), 7.65-7.70 (m, 2H); MS [M-Br]⁺: 456; mp 221° C.

EXAMPLE 1383(R)-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-1-(3-thien-2-ylpropyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 310 mg, 97%. ¹H-NMR (DMSO-d6): δ 1.30 (m, 1H),1.62 (m, 1H), 1.70-1.90 (m, 4H), 2.05 (m, 1H), 2.60 (m, 1H), 2.75-2.85(m, 4H), 3.15 (m, 2H), 3.25-3.40 (m, 2H), 3.75 (m,1H), 5.0 (m, 1H), 6.93(m,1H) 7.0 (m, 1H), 7.14-7.26 (m, 5H), 7.36-7.45 (m, 3H), 7.63-7.67 (m,2H); MS [M-Br]⁺: 476; mp 111° C.

EXAMPLE 1393(R)-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 85 mg, 41%. ¹H-NMR (DMSO-d6): δ 1.30 (m, 1H),1.65 (m, 1H), 1.70-1.95 (m, 2H), 2.05 (m, 1H), 2.5-2.6 (m, 2H), 2.80 (m,1H), 3.05-3.75 (m, 7H), 5.05 (m, 1H), 7.1-7.45 (m, 12H), 7.65-7.70 (m,2H); MS [M-CF3COO]⁺: 470.

EXAMPLE 1403(R)-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-1-(4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 84 mg, 38%. ¹H-NMR (DMSO-d6): δ 1.30 (m, 1H),1.4-1.85 (m, 7H), 2.05 (m, 1H), 2.5-2.6 (m, 2H), 2.80 (m, 1H), 3.05-3.4(m, 6H), 3.7 (m, 1H), 5.05 (m, 1H), 7.15-7.35 (m, 10H), 7.4 (m, 1H),7.65 (m, 2H); MS [M-CF3COO]⁺: 484.

EXAMPLE 1413(R)-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-1-(2-thien-2-ylethyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 81 mg, 39%. ¹H-NMR (DMSO-d6): δ 1.30 (m, 1H),1.6 (m, 1H), 1.7-1.9 (m, 2H), 2.05 (m, 1H), 2.75 (m, 1H), 3.0 (m, 1H),3.1-3.2 (m, 2H), 3.3-3.6 (m, 5H), 3.8 (m, 1H), 5.05 (m, 1H), 6.95-7.0(m, 2H), 7.15-7.3 (m, 5H), 7.45 (m, 3H), 7.65 (m, 2H); MS [M-CF3COO]⁺:462.

EXAMPLE 1423(R)-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-1-(4-phenoxybutyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 83 mg, 37%. ¹H-NMR (DMSO-d6): δ 1.3 (m, 1H),1.5-1.9 (m, 7H), 2.05 (m, 1H), 2.6 (m, 1H), 2.8 (m, 1H), 3.1-3.45 (m,7H), 3.75 (m, 1H), 4.0 (m, 2H), 5.05 (m, 1H), 6.95-7.0 (m, 3H),7.15-7.45 (m, 9H), 7.65 (m, 2H); MS [M-CF3COO]⁺: 500.

EXAMPLE 1433(R)-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 102 mg, 48%. ¹H-NMR (DMSO-d6): δ 1.3 (m, 1H),1.55-1.95 (m, 3H), 2.05 (m, 1H), 2.8 (m, 1H), 3.1 (m, 1H), 3.35-3.65 (m,5H), 3.9 (m, 1H), 4.35 (m, 2H), 5.05 (m, 1H), 6.95 (d, 2H), 7.0-7.1 (m,2H), 7.2 (m, 4H), 7.3-7.45 (m, 4H), 7.6 (t, 2H); MS [M-CF3COO]⁺: 472.

EXAMPLE 1441-[3-(4-Fluorophenoxy)propyl]-3(R)-(9-hydroxy-9H-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 99 mg, 44%. ¹H-NMR (DMSO-d6): δ 1.3 (m, 1H), 1.6(m, 1H), 1.7-2.0 (m, 4H), 2.05 (m, 1H), 2.7 (m, 1H), 2.9 (m, 1H),3.2-3.5 (m, 5H), 3.75-3.85 (m, 1H), 3.95 (m, 2H), 5.0 (m, 1H), 6.95 (m,2H), 7.1-7.3 (m, 7H), 7.45 (t, 2H), 7.65 (t, 2H); MS [M-CF3COO]⁺: 504.

EXAMPLE 1453(R)-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-1-(3-phenylallyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 25 mg, 12%. ¹H-NMR (DMSO-d6): δ 1.25-1.30 (m,1H), 1.55-1.95 (m, 3H), 2.10 (m, 1H), 2.65-2.75 (m, 1H), 2.9 (m, 1H),3.25-3.50 (m, 2H), 3.75-3.8 (m, 1H), 3.95 (m, 2H), 4.2 (d, 1H), 5.0 (m,1H), 6.35 (m, 1H), 6.80 (d, 1H), 7.05-7.50 (m, 8H), 7.60 (m, 4H); MS[M-CF3COO]⁺: 468.

EXAMPLE 1463(R)-(9-Methyl-9[H]-xanthene-9-carbonyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods c and a. Theyield of final step was 110 mg. ¹H-NMR (DMSO-d6): δ 1.4 (m, 1H), 1.65(m, 1H), 1.75-1.95 (m, 2H), 1.9 (s, 3H), 2.05-2.15 (m, 3H), 1.8 (m, 1H),3.15 (m, 2H), 3.25-3.5 (m, 5H), 3.85 (m, 1H), 4.0 (t, 2H), 5.05 (m, 1H),6.95-7.0 (m, 3H), 7.15-7.2 (m, 4H), 7.3-7.4 (m, 4H), 7.45 (d, 1H), 7.55(d, 1H); MS [M-Br]⁺: 484; mp 195° C.

EXAMPLE 1473(R)-(9-Methyl-9[H]-xanthene-9-carbonyloxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 19 mg, 20%. ¹H-NMR (DMSO-d6): δ 1.4 (m, 1H),1.65 (m, 1H), 1.8-1.95 (m, 2H), 1.9 (s, 3H), 2.15 (m, 1H), 2.8-2.95 (m,3H), 3.15 (d, 1H), 3.3-3.5 (m, 5H), 4.9 (m, 1H), 5.1 (m, 1H), 7.15 (m,4H), 7.25-7.4 (m, 7H), 7.45 (d, 1H), 7.55 (d, 1H); MS [M-CF₃COO]⁺: 454.

EXAMPLE 1483(R)-(9-Methyl-9[H]-xanthene-9-carbonyloxy)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 24 mg, 24%. ¹H-NMR (DMSO-d6): δ 1.4 (m, 1H),1.65 (m, 1H), 1.8-1.95 (m, 2H), 1.9 (s, 3H), 2.15 (m, 1H), 2.95 (m, 1H),3.25 (m, 1H), 3.4-3.65 (m, 5H), 3.85 (m, 1H), 4.35 (t, 2H), 5.05 (m,1H), 6.95 (d, 2H), 7.05 (t, 2H), 7.15 (m, 3H), 7.25-7.45 (m, 6H); MS[M-CF₃COO]⁺: 470.

EXAMPLE 1493(R)-(9-Methyl-9[H]-xanthene-9-carbonyloxy)-1-(4-oxo-4-phenylbutyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 19 mg, 19%. ¹H-NMR (DMSO-d6): δ 1.4 (m, 1H),1.65 (m, 1H), 1.75-1.95 (m, 7H), 2.15 (m, 1H), 2.8 (m, 1H), 3.05-3.25(m, 4H), 3.3-3.5 (m, 4H), 3.85 (m, 1H), 5.05 (m, 1H), 7.15 (m, 4H), 7.35(t, 2H), 7.45-7.6 (m, 4H), 7.7 (t, 1H), 8.0 (d, 2H); MS [M-CF₃COO]⁺:496.

EXAMPLE 1501-[3-(4-Fluorophenoxy)propyl]-3(R)-(9-methyl-9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 25 mg, 24%. ¹H-NMR (DMSO-d6): δ 1.4 (m, 1H),1.65 (m, 1H), 1.75-1.95 (m, 2H), 1.9 (s, 3H), 1.95-2.1 (m, 2H), 2.15 (m,1H), 2.8 (m, 1H), 3.1 (d, 1H), 3.25-3.5 (m, 5H), 3.8 (m, 1H), 4.0 (t,2H), 5.05 (m, 1H), 6.95 (m, 2H), 7.15 (m, 6H), 7.35 (t, 2H), 7.5 (dd,2H); MS [M-CF₃COO]⁺: 502.

EXAMPLE 1511-[3-(2,4-Difluorophenoxy)propyl]-3(R)-(9-methyl-9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 16 mg, 15%. ¹H-NMR (DMSO-d6): δ 1.4 (m, 1H),1.65 (m, 1H), 1.75-1.95 (m, 2H), 1.9 (s, 3H), 2.0-2.15 (m, 3H), 2.8 (m,1H), 3.1 (d, 1H), 7.05 (t, 1H), 7.1-7.4 (m, 8H), 7.5 (dd, 2H); MS[M-CF₃COO]⁺: 520.

EXAMPLE 1523(R)-(9-Methyl-9[H]-xanthene-9-carbonyloxy)-1-(3-phenylaminopropyl)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 16 mg, 15%. ¹H-NMR (DMSO-d6): δ 1.35 (m, 1H),1.6 (m, 1H), 1.7-1.9 (m, 4H), 1.9 (s, 3H), 2.1 (m, 1H), 2.7 (m, 1H),2.95-3.05 (m, 3H), 3.1-3.4 (m, 6H), 3.75 (m, 1H), 5.0 (m, 1H), 5.6 (m,1H), 6.55 (m, 3H), 7.05-7.15 (m, 6H), 7.3 (m, 2H), 7.45 (t, 2H); MS[M-CF₃COO]⁺: 483.

EXAMPLE 1531-[3-(4-Hydroxyphenoxy)propyl]-3(R)-(9-methyl-9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 19 mg, 18%. ¹H-NMR (DMSO-d6): δ 1.4 (m, 1H),1.65 (m, 1H), 2.75-2.05 (m, 4H), 1.9 (s, 3H), 2.15 (m, 1H), 2.8 (m, 1H),3.1 (d, 1H), 3.25-3.5 (m, 5H), 3.8-3.95 (m, 3H), 5.05 (m, 1H), 6.65-6.8(m, 4H), 7.2 (m, 4H), 7.35 (t, 2H), 7.5 (m, 2H), 9.0 (s, OH); MS[M-CF₃COO]⁺: 500.

EXAMPLE 1541-(2-Benzyloxyethyl)-3(R)-(9-methyl-9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;trifluoroacetate

The title compound was synthesised according to methods c and b. Theyield of final step was 14 mg, 14%. ¹H-NMR (DMSO-d6): δ 1.4 (m, 1H),1.65 (m, 1H), 1.75-1.95 (m, 2H), 1.9 (s, 3H), 2.1 (m, 1H), 2.9 (m, 1H),3.2-3.5 (m, 6H), 3.75-3.95 (m, 3H), 4.5 (s, 2H), 5.05 (m, 1H), 7.15 (m,4H), 7.3-7.5 (m, 9H); MS [M-CF₃COO]⁺: 484.

EXAMPLE 1551-(3-Phenoxypropyl)-3(R)-(9[H]-thioxanthene-9-carbonyloxy)-1-azonia-bicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods d and a. Theyield of final step was 323 mg, 50%. ¹H-NMR (DMSO-d6): δ 1.35 (m, 1H),1.65 (m, 1H), 1.70-1.95 (m, 2H), 2.0-2.2 (m, 3H), 2.75-2.90 (m, 1H),3.12 (m, 1H), 3.25-3.50 (m, 5H), 3.80 (m, 1H), 4.0 (t, 2H), 5.0 (m, 1H),5.6 (s, 1H), 6.94-7.0 (m, 3H), 7.22-7.41 (m, 6H), 7.45-7.64 (m, 4H); MS[M-Br]⁺: 486; mp 157° C.

EXAMPLE 1561-(3-phenylallyl)-3(R)-(10,11-Dihydro-5H-dibenzo[a,d]cycloheptene-5-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods d and a. Theyield of final step was 250 mg, 94%. ¹H-NMR (CDCl₃): δ 1.50-1.60 (m,1H), 1.60-1.80 (m, 1H), 1.90 (m, 2H), 2.30 (m, 1H), 2.65-2.80 (m, 2H),2.90-3.20 (m, 3H), 3.50 (d, 1H), 3.60-3.90 (m, 3H), 4.20 (m, 1H),4.35-4.60 (double dd, 2H), 5.10 (m, 1H), 5.15 (s, 1H), 6.05 (dd, 1H),6.90-7.0 (m, 2H), 7.0-7.5 (m, 11H); MS [M-Br]⁺: 464; mp 132° C.

EXAMPLE 1571-(3-phenoxypropyl)-3(R)-(10,11-Dihydro-5H-dibenzo[a,d]cycloheptene-5-carbonyloxy)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods d and a. Theyield of final step was 290 mg, 94%. ¹H-NMR (CDCl₃): δ 1.45-1.60 (m,1H), 1.65-1.80 (m, 1H), 1.80-2.0 (m, 2H), 2.0-2.20 (m, 3H), 2.80-3.0 (m,3H), 3.15-3.30 (m, 2H), 3.30-3.45 (d, 1H), 3.45-3.80 (m, 5H), 3.85-4.0(m, 2H), 4.20 (m, 1H), 5.10 (m, 1H), 5.20 (s, 1H), 6.80-6.90 (d, 2H),6.90-7.0 (t, 1H), 7.10-7.30 (m, 8H), 7.40 (m, 2H); MS [M-Br]⁺: 482; mp182° C.

EXAMPLE 1583(R)-(5[H]-Dibenzo[a,d]cycloheptene-5-carbonyloxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods d and a. Theyield of final step was 180 mg, 56%. ¹H-NMR (DMSO-d6) δ 1.2 (m, 1H), 1.6(m, 1H), 1.7-1.9 (m, 2H), 1.95 (m, 1H), 2.1 (m, 2H), 2.8 (m, 1H), 2.95(d, 1H), 3.25-3.45 (m, 5H), 3.8 (m, 1H), 4.05 (t, 2H), 4.9 (m, 1H), 5.45(s, 1H), 6.9-7.1 (m, 5H), 7.3-7.5 (m, 9H), 7.55 (d, 2H); MS [M-Br]⁺:480; mp 1111 C.

EXAMPLE 1593(R)-(5[H]-Dibenzo[a,d]cycloheptene-5-carbonyloxy)-1-phenethyl-1-azoniabicyclo[2.2.2]octane;bromide

The title compound was synthesised according to methods d and a. Theyield of final step was 210 mg, 68%. ¹H-NMR (DMSO-d6): δ 1.2 (m, 1H),1.7-1.9 (m, 2H), 2.0 (m, 1H), 2.85-3.1 (m, 4H), 3.3-3.5 (m, 5H), 3.85(m, 1H), 4.95 (m, 1H), 5.45 (s, 1H), 7.05 (m, 2H), 7.25-7.5 (m, 11H),7.55 (m, 2H); MS [M-Br]⁺: 450; mp 2481 C.

The Examples 160 to 164 illustrate pharmaceutical compositions accordingto the present invention and procedure for their preparation.

EXAMPLE 160 Preparation of a Pharmaceutical Composition: Tablets

Formulation:

Compound of the present invention 5.0 mg Lactose 113.6 mgMacrocrystalline cellulose 28.4 mg Light silicic anhydride 1.5 mgMagnesium stearate 1.5 mg

Using a mixer machine, 15 g of the compound of the present invention wasmixed with 340.8 g of lactose and 85.2 g of microcrystalline cellulose.The mixture was subjected to compression moulding using a rollercompactor to give a flake-like compressed material. The flake-likecompressed material was pulverized using a hammer mill, and thepulverized material was screened through a 20 mesh screen. A 4.5 gportion of light silicon anhydride and 4.5 g of magnesium stearate wereadded to the screened material and mixed. The mixer product wassubjected to a tablets making machine equipped with a die/punch systemof 7.5 mm in diameter, thereby obtaining 3,000 tablets each having 150mg in weight.

EXAMPLE 161 Preparation of a Pharmaceutical Composition: Tablets Coated

Formulation:

Compound of the present invention 5.0 mg Lactose 95.2 mg Corn starch40.8 mg Polyvinylpyrrolidone K25 7.5 mg Magnesium stearate 1.5 mgHydroxypropylcellulose 2.3 mg Polyethylene glycol 6000 0.4 mg Titaniumdioxide 1.1 mg Purified talc 0.7 mg

Using a fluidized bed granulating machine, 15 g of the compound of thepresent invention was mixed with 285.6 g of lactose and 122.4 g of cornstarch. Separately, 22.5 g of polyvinylpyrrolidone was dissolved in127.5 g of water to prepare a binding solution. Using a fluidized bedgranulating machine, the binding solution was sprayed on the abovemixture to give granulates. A 4.5 g portion of magnesium stearate wasadded to the obtained granulates and mixed. The obtained mixture wassubjected to a tablet making machine equipped with a die/punch biconcavesystem of 6.5 mm in diameter, thereby obtaining 3,000 tablets, eachhaving 150 mg in weight.

Separately, a coating solution was prepared by suspending 6.9 g ofhydroxypropylmethylcellulose 2910, 1.2 g of polyethylene glycol 6000,3.3 g of titanium dioxide and 2.1 g of purified talc in 72.6 g of water.Using a High Coated, the 3,000 tablets prepared above were coated withthe coating solution to give film-coated tablets, each having 154.5 mgin weight.

EXAMPLE 162 Preparation of a Pharmaceutical Composition: Liquid Inhalant

Formulation:

Compound of the present invention 400 Φg Physiological saline 1 ml

A 40 mg portion of the compound of the present invention was dissolvedin 90 ml of physiological saline, and the solution was adjusted to atotal volume of 100 ml with the same saline solution, dispensed in 1 mlportions into 1 ml capacity ampoule and then sterilized at 1151 for 30minutes to give liquid inhalant.

EXAMPLE 163 Preparation of a Pharmaceutical Composition: Powder Inhalant

Formulation:

Compound of the present invention 200 Φg Lactose 4,000 Φg

A 20 g portion of the compound of the present invention was uniformlymixed with 400 g of lactose, and a 200 mg portion of the mixture waspacked in a powder inhaler for exclusive use to produce a powderinhalant.

EXAMPLE 164 Preparation of a Pharmaceutical Composition: InhalationAerosol

Formulation:

Compound of the present invention 200 Φg Dehydrated (Absolute) ethylalcohol USP 8,400 Φg 1,1,1,2-Tetrafluoroethane (HFC-134A) 46,810 Φg

The active ingredient concentrate is prepared by dissolving 0.0480 g ofthe compound of the present invention in 2.0160 g of ethyl alcohol. Theconcentrate is added to an appropriate filling apparatus. The activeingredient concentrate is dispensed into aerosol container, theheadspace of the container is purged with Nitrogen or HFC-134A vapor(purging ingredients should not contain more than 1 ppm oxygen) and issealed with valve. 11.2344 g of HFC-134A propellant is then pressurefilled into the sealed container.

1. A compound which is3(R)-1-phenethyl-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octane wherein an anion X⁻ is associated with the positive charge of thenitrogen atom and wherein X⁻ is a pharmaceutically acceptable anion of amono- or polyvalent acid.
 2. The compound according to claim 1 which is3(R)-1-phenethyl-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octanebromide.
 3. A pharmaceutical composition comprising a compound accordingto claim 1 in admixture with a pharmaceutically acceptable carrier ordiluent.
 4. The pharmaceutical composition of claim 3 comprising3(R)-1-phenethyl-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octanebromide.
 5. A method for treating chronic obstructive pulmonary disease,chronic bronchitis, bronchial hyperreactivity, asthma, or rhinitis whichmethod comprises administering to a human or animal patient in need ofsuch treatment an effective amount of a compound according to claim 1.6. The method according to claim 5 comprising administering to thepatient an effective amount3(R)-1-phenethyl-(9[H]-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octanebromide.